Billy Loo, MD

Abstract

The application of radio frequency (RF) vacuum electronics for the betterment of the human condition began soon after the invention of the first vacuum tubes in the 1920s and has not stopped since. Today, microwave vacuum devices are powering important applications in health treatment, material and biological science, wireless communication-terrestrial and space, Earth environment remote sensing, and the promise of safe, reliable, and inexhaustible energy. This article highlights some of the exciting application frontiers of vacuum electronics.

View details for DOI 10.1109/ted.2023.3239841

View details for PubMedID 37250956

View details for PubMedCentralID PMC10216895

Abstract

We present the case of a woman with metastatic adenoid cystic carcinoma who received stereotactic ablative radiotherapy (SABR) with a total dose of 50 Gy in 4 fractions to two lung metastases and developed symptomatic left phrenic nerve injury 2 years after radiation. The maximum dose to the approximate location of the phrenic nerve was 57.7 Gy which corresponds to a biologically effective dose for late effects (using / ratio=3) of 335.14 Gy. Here, we discuss the case, planning considerations by radiation oncologists and medical physicists, and the multidisciplinary medical management of this patient.

View details for DOI 10.1016/j.prro.2023.04.010

View details for PubMedID 37150318

Abstract

Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

View details for DOI 10.1016/j.jtho.2023.04.007

View details for PubMedID 37085030

Abstract

The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O 2 ) and hypoxic conditions (2% O 2 ) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O 2 ) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing ( HTGTS-JoinT-seq ), using S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1*10 2 -5*10 6 Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

View details for DOI 10.1101/2023.03.27.534408

View details for PubMedID 37034651

Abstract

The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC.Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment.We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%).At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

View details for DOI 10.3389/fonc.2023.1139940

View details for PubMedID 37035171

View details for PubMedCentralID PMC10080021

View details for DOI 10.1109/TED.2023.3239841

View details for Web of Science ID 000947833100001

Abstract

Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

View details for DOI 10.1200/PO.22.00273

View details for PubMedID 36603171

Abstract

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

View details for DOI 10.6004/jnccn.2023.0045

View details for PubMedID 37673108

Abstract

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

View details for DOI 10.6004/jnccn.2023.0020

View details for PubMedID 37015337

Abstract

INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

View details for DOI 10.1016/j.ctarc.2022.100659

View details for PubMedID 36427429

View details for Web of Science ID 000892639302166

View details for Web of Science ID 000892639301234

View details for Web of Science ID 000892639302305

View details for Web of Science ID 000892639301258

View details for Web of Science ID 000847787800093

View details for Web of Science ID 000847787800071

View details for Web of Science ID 000858678100059

View details for Web of Science ID 000847787800034

Abstract

Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.

View details for DOI 10.1016/j.prro.2022.06.013

View details for PubMedID 35858658

View details for Web of Science ID 000808579201032

View details for Web of Science ID 000808579201005

View details for Web of Science ID 000808579202043

Abstract

Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with 3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had 3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.

View details for DOI 10.1016/j.ijrobp.2022.04.050

View details for PubMedID 35654305

Abstract

INTRODUCTION/BACKGROUND: Differentiating local recurrence (LR) from post-treatment changes following stereotactic ablative radiotherapy (SABR) for thoracic tumors is challenging. We sought to evaluate the performance of FDG-PET-CT in distinguishing recurrence from post-radiation changes in patients with stage I-II non-small cell lung cancer (NSCLC) treated with SABR.MATERIALS AND METHODS: We performed a retrospective review of patients with stage I-II NSCLC treated with SABR and subsequently followed with surveillance FDG-PET-CT scans from 2004 to 2014. The radiology reports were coded as 0 or 1 if minimally or substantially concerning for LR, respectively, and correlated with outcome. Prognostic factors for false-positive FDG-PET-CT were assessed using logistic regression models.RESULTS: We identified 145 patients meeting inclusion criteria for the retrospective analysis. Amongst the 39 (26.9%) patients with FDG-PET-CT scans concerning for LR 3 to 24 months after treatment, 14 were confirmed to have LR. Thus, the positive predictive value (PPV) of FDG-PET-CT in identifying LR was 36% (14/39). Factors associated with a false-positive scan included concerning FDG-PET-CT at the earliest post-treatment time point (3 months) (odds ratio 0.67, P= .04) and older age (odds ratio 2.3, P= .02).CONCLUSION: Our analysis indicates that the PPV of a concerning FDG-PET-CT after SABR for early-stage NSCLC is relatively low, especially at early post-treatment timepoints, but accuracy is improving over time with institutional experience.

View details for DOI 10.1016/j.cllc.2022.01.006

View details for PubMedID 35246393

Abstract

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

View details for DOI 10.6004/jnccn.2022.0025

View details for PubMedID 35545176

Abstract

PURPOSE: To evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with stereotactic ablative radiotherapy (SABR).METHODS AND MATERIALS: Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an alpha/SS ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.RESULTS: Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade), 28 with PTV overlapping the esophagus. Median follow-up and overall survival were 16 and 23 months respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1-3 months in 12 patients, and 6 months in all patients. No grade 3-5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. Cumulative incidence of acute esophagitis was 15% and 25% at 14 days and 60 days respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) < 62 Gy, D1cc (BED10) < 48 Gy, D2cc (BED10) < 43 Gy, and Dmax/Dprescription < 85% was associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred.CONCLUSIONS: Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

View details for DOI 10.1016/j.ijrobp.2021.12.008

View details for PubMedID 34942312

Abstract

PURPOSE/OBJECTIVE(S): Rapid and accurate estimation of tumor burden in biomedical images is essential for precisely monitoring cancer progression and assessing therapeutic response. The ability to detect and segment tumors using an automated approach is a key part of this task. Despite recent advances from deep learning, lung tumor delineation remains challenging, particularly when the tumor bounding box is not provided to the model. We hypothesized that clinical radiation oncology contours could supply a large enough dataset of 3D tumor segmentations to enable more accurate models. We developed and validated a deep learning-based model to identify and segment primary and metastatic lung tumors on computed tomography (CT) images.MATERIALS/METHODS: We curated a dataset consisting of CT images and clinical segmentations of 1,916 lung tumors in 1,504 patients who received radiation treatment for one or more primary or metastatic lung tumors. Segmentation quality was independently verified by a radiation oncologist using a custom web application. This dataset was used to train two 3D U-Net convolutional neural networks with varying model properties: one using high-resolution and small input volumes, and one using low-resolution and large input volumes. Models were ensembled together during validation. Performance was evaluated using an external held-out test set of CT images and segmentations from 59 patients with a single primary or metastatic lung tumor, treated at a separate clinical site. This test set consisted of 50 primary lung cancers and 9 metastases. To benchmark model performance against physicians, the test set was also contoured by two additional radiation oncologists.RESULTS: Median tumor volume in the external test set was 80.48 cubic centimeters (interquartile range [IQR]: 14.40 to 177.65). The segmentations generated by the ensembled model produced a mean Dice coefficient of 0.62 (IQR: 0.47 to 0.85) on the test set. The sensitivity for detecting a tumor, as defined by correctly predicting at least one voxel within a ground truth tumor, was 93.2%, and the Dice coefficient for the scans with correctly identified lesions was 0.67 (IQR: 0.53 to 0.85). In comparison, the mean interobserver Dice coefficient for the three physicians on the test set was 0.76 (IQR: 0.70 to 0.84). We observed strong correlation between physician-determined tumor size and model-predicted tumor size (Pearson correlation, r=0.69, P < 0.0001).CONCLUSION: An end-to-end deep learning-based model was able to identify and segment lung tumors in a completely automated fashion, with near-expert level performance. Such models could soon be useful for clinical contouring and automatic quantification of tumor burden.

View details for DOI 10.1016/j.ijrobp.2021.07.476

View details for PubMedID 34702000

Abstract

PURPOSE/OBJECTIVE(S): Hemoptysis is a rare but potentially fatal toxicity associated with thoracic stereotactic ablative radiotherapy (SABR). Prior studies have suggested that vascular endothelial growth factor inhibitors (VEGFI) may potentiate the risk for pulmonary hemorrhage in patients treated with SABR for centrally located lung tumors. To what degree the risk of toxicity varies by timing of therapies or tumor location is uncertain. The purpose of this study is to evaluate the combined toxicity of VEGFIs and SABR for peripheral, central, or ultra-central tumors.MATERIALS/METHODS: We evaluated patients with primary or metastatic lung tumors treated with SABR between 2008 and 2018 at a single institution. Baseline patient, tumor and treatment characteristics were evaluated. Pulmonary bleeding events were graded using CTCAE version 5.0. Rates of a grade three or higher (G3+) or any ipsilateral pulmonary hemorrhage at three years were estimated using the Kaplan-Meier method. We compared rates of bleeding by tumor location, treatment with a VEGFI, sequence of therapy and VEGFI within 90 days of SABR using the log-rank test.RESULTS: This retrospective cohort study included a total of 925 pulmonary tumors treated with SABR in 691 patients. There were 44 patients treated with a VEGFI (bevacizumab, sorafenib, pazopanib, sunitinib or ramucirumab), with the majority receiving bevacizumab (n=38, 86.3%). Among those treated with a VEGFI, the median interval between VEGFI therapy and SABR was 16 weeks, ranging from zero days to 3.7 years, with 15 (34.0%) patients treated within 90 days of SABR. Patients were treated with SABR to peripheral (738, 79.8%), central (137, 14.8%) and ultra-central (50, 5.4%) locations with a median BED10 of 87.5 Gy. Median follow-up was 32.2 months for the overall cohort and 46.4 months for VEGFI patients. The rate of G3+ hemorrhage was significantly higher in patients treated with a VEGFI (7.3 vs 0.8%, P < 0.01). The rate of any grade hemorrhage did not significantly vary between groups (9.4 vs 2.7%, P=0.1). When stratified by location, both central/ultra-central tumors (21.1 vs 3.2%, P=0.03) and peripheral tumors (3.4 vs 0.1%, P=0.03) had increased rates of G3+ hemorrhage when treated with a VEGFI. Among patients treated with SABR and VEGFI, there was no significant difference in rates of hemorrhage when the interval was > or 90 days (12.0 vs 0.0%, P=0.17). Similarly, there was no significant difference between rates of G3+ hemorrhage when VEGFI was given before (12.9%), after (8.3%), or before and after SABR (0.0%).CONCLUSION: VEGFI therapy was associated with an increased rate of high-grade hemorrhage in patients undergoing SABR to pulmonary tumors. Rates of high-grade hemorrhage were increased with VEGFI for both central/ultra-central and peripheral tumors although the absolute rate was low for peripheral tumors. While limited by low sample size and event rate, there was no correlation observed between interval or sequence of VEGFI and SABR and rate of high-grade hemorrhage.

View details for DOI 10.1016/j.ijrobp.2021.07.1208

View details for PubMedID 34701419

View details for Web of Science ID 000715803800288

View details for Web of Science ID 000715803801616

View details for Web of Science ID 000715803801402

View details for Web of Science ID 000715803800920

View details for Web of Science ID 000715803800145

View details for Web of Science ID 000715803801515

Abstract

PURPOSE/OBJECTIVE(S): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.MATERIALS/METHODS: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.RESULTS: The observational cohort included N=433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).CONCLUSION: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation.

View details for DOI 10.1016/j.ijrobp.2021.07.1262

View details for PubMedID 34701476

View details for Web of Science ID 000715803800895

View details for Web of Science ID 000715803800868

Abstract

PURPOSE/OBJECTIVE(S): Navigating cancer care is a major life stressor and negative determinant of cancer patient quality of life and potentially patient satisfaction. Patient education has been shown to ameliorate these negative outcomes, but this has proven difficult in the field of radiation oncology. One obstacle for effective patient education in radiation oncology is the inherent difficulty of explaining a visual spatial treatment paradigm using traditional verbal or written teaching aids. However, existing visual patient education platforms are lacking in key areas including fidelity to patient experience, cost, scalability and generalizability. In that context, the present study presents a cheap, immersive, realistic, and scalable smartphone-based virtual reality interface where patients can learn about and visually experience their treatment from anywhere using almost any modern smartphone.MATERIALS/METHODS: We utilized a Ricoh Theta V 360-degree camera to capture immersive spherical still images and videos of various parts of the patient experience, including simulation, Klarity mask-making, and the treatment vault. Images and videos were uploaded and processed in the Google environment (Google Photos and YouTube, respectively). The smartphone-based virtual reality experience was accomplished using various IOS and android devices attached to inexpensive Google Cardboard-compatible headsets. Separately, the VR experience was tested on an Oculus Quest 2 device as well.RESULTS: Images and videos were quick and easy to obtain (initial proof-of-concept was accomplished within 3 hours), and the approach was tractable for even those with limited audiovisual experience. The immersive images and videos were subjectively tested and validated by multiple investigators on the Oculus Platform as well as the Google Cardboard Platform using both IOS and Android devices as reliably representing the chosen aspect of treatment. The overall cost required to add the VR equipment to any existing smartphone was under $15 using commercially-available components.CONCLUSION: The present study describes a VR-based radiation oncology patient education experience that is inexpensive and modular to nearly any institution or clinical scenario. The already nominal cost can potentially be driven lower by 3D printing or similar customization. Moreover, patients can engage the simulation from anywhere with minimal assistance needed. The present proof-of-concept study has the potential to increase patient quality of life, treatment compliance and satisfaction all while reducing stress. Furthermore, the current global pandemic underscores the need for remote education resources both now and in the future. To these ends, this approach is currently being prospectively validated for impact on patient knowledge, satisfaction, stress and quality of life endpoints.

View details for DOI 10.1016/j.ijrobp.2021.07.621

View details for PubMedID 34700803

Abstract

PURPOSE/OBJECTIVE(S): Ultra-high dose rate (FLASH) radiotherapy (RT) at 40 Gray per second has been shown preclinically to achieve improved normal tissue sparing while maintaining tumor control similar to that of conventional dose-rate RT. Many published FLASH-RT delivery models are inaccessible for widespread use and/or not applicable for clinical translation. We previously described a model for reversible configuration of a clinical linear accelerator (LINAC) that can deliver 16-18 MeV electron FLASH-RT at source-to-surface distances (SSDs) < 95 cm. However, it precludes the use of a standard electron cone. This proof-of-concept study will characterize the beam profiles from a novel cone-less set-up, to verify its feasibility as a widely accessible method of electron FLASH-RT delivery for the intention of clinical treatment.MATERIALS/METHODS: This novel set-up employs a flat 25*25 cm applicator with custom cut-outs that lies within the accessory mount at 66.6 cm SSD of a standard treatment delivery system. We tested a 10*10 cm circular field size at a target distance of 80 cm SSD (selected to maintain FLASH dose rates). Radiographic film and an IC Profiler were used to evaluate penumbra width, beam flatness, symmetry, and percentage depth dose (PDD). FLASH-RT was delivered in 20 pulses with 3 independent measurements each using film and the profiler. This was compared to a conventional 16 MeV beam using a standard cone with a 10*10 cm field size at 100 cm SSD.RESULTS: Our novel cone-less FLASH set-up achieved a beam profile that was similar to the conventional electron set-up. Respectively, for the cone-less and conventional set-up, measured at a standardized depth of half R85, penumbra width was 1.13 cm and 1.15 cm, and uniformity index was 0.72 and 0.74 (defined as the ratio of the areas inside the 90% and 50% isodose lines); measured at a standardized depth of R95, flatness (defined as the maximum dose deviation from the central axis at a specific depth over an area confined within lines 2 cm inside the geometric edge of fields) was 1.5% and 4.1%, beam diameter containing dose > 80% of the central axis was 10.6 cm and 9.6 cm, and symmetry (defined as the maximum dose difference between any two symmetric points about the central axis in the flat portion of the beam, as a percentage of central dose) was 2.24% and 2.20%. PDD values for the cone-less set-up at Dmax, R95, R85, and R50 were, respectively, 3.1, 4.1, 5.3, and 6.8 cm.CONCLUSION: We have developed a novel cone-less set-up that allows for the delivery of electron FLASH-RT utilizing a clinical LINAC at practical SSDs and verified that its beam profiles are clinically feasible. Further work will be done to characterize additional SSDs and field sizes, along with the addition of a custom skin collimator to further shape the beam. This will pave the way for practical treatment using electron FLASH-RT to a host of oncologic indications, including cutaneous malignancies and partial breast irradiation in the future.

View details for DOI 10.1016/j.ijrobp.2021.07.314

View details for PubMedID 34700478

Abstract

PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: 10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

View details for DOI 10.1016/j.ijrobp.2021.07.212

View details for PubMedID 34700657

Abstract

PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n=214), T2 (25.4%, n=87) and T3 (12.0%, n=41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P=0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n=8), chemotherapy and RT (CRT) (43.3 %, n=13), chemotherapy alone (13.3%, n=4) or observation (16.7%, n=5). RT regimens included standard fractionation (38.0%, n=8), hypofractionation (52.4%, n=11) or SABR (9.5%, n=2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

View details for DOI 10.1016/j.ijrobp.2021.07.1235

View details for PubMedID 34701446

View details for DOI 10.1016/j.jtho.2021.06.030

View details for PubMedID 34561039

View details for Web of Science ID 000701779700174

View details for Web of Science ID 000701779700169

Abstract

PURPOSE: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR).MATERIALS AND METHODS: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk.RESULTS: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using alpha/beta ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively).CONCLUSIONS: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.

View details for DOI 10.1097/COC.0000000000000864

View details for PubMedID 34534143

Abstract

Radiomics refers to the high-throughput extraction of quantitative features from radiological scans and is widely used to search for imaging biomarkers for prediction of clinical outcomes. Current radiomic signatures suffer from limited reproducibility and generalizability, because most features are dependent on imaging modality and tumor histology, making them sensitive to variations in scan protocol. Here, we propose novel radiological features that are specially designed to ensure compatibility across diverse tissues and imaging contrast. These features provide systematic characterization of tumor morphology and spatial heterogeneity. In an international multi-institution study of 1,682 patients, we discover and validate four unifying imaging subtypes across three malignancies and two major imaging modalities. These tumor subtypes demonstrate distinct molecular characteristics and prognoses after conventional therapies. In advanced lung cancer treated with immunotherapy, one subtype is associated with improved survival and increased tumor-infiltrating lymphocytes compared with the others. Deep learning enables automatic tumor segmentation and reproducible subtype identification, which can facilitate practical implementation. The unifying radiological tumor classification may inform prognosis and treatment response for precision medicine.

View details for DOI 10.1038/s42256-021-00377-0

View details for PubMedID 34841195

View details for PubMedCentralID PMC8612063

View details for DOI 10.1038/s42256-021-00377-0

View details for Web of Science ID 000685037800005

Abstract

OBJECTIVE: Lobectomy is a standard treatment for stage I non-small cell lung cancer, but a significant proportion of patients are considered at high risk for complications, including mortality, after lobectomy and might not be candidates. Identifying who is at risk is important and in evolution. The objective of The American Association for Thoracic Surgery Clinical Practice Standards Committee expert panel was to review important considerations and factors in assessing who is at high risk among patients considered for lobectomy.METHODS: The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an expert panel that developed an expert consensus document after systematic review of the literature. The expert panel generated a priori a list of important risk factors in the determination of high risk for lobectomy. A survey was administered, and the expert panel was asked to grade the relative importance of each risk factor. Recommendations were developed using discussion and a modified Delphi method.RESULTS: The expert panel survey identified the most important factors in the determination of high risk, which included the need for supplemental oxygen because of severe underlying lung disease, low diffusion capacity, the presence of frailty, and the overall assessment of daily activity and functional status. The panel determined that factors, such as age (as a sole factor), were less important in risk assessment.CONCLUSIONS: Defining who is at high risk for lobectomy for stage I non-small cell lung cancer is challenging, but remains critical. There was impressive strong consensus on identification of important factors and their hierarchical ranking of perceived risk. The panel identified several key factors that can be incorporated in risk assessment. The factors are evolving and as the population ages, factors such as neurocognitive function and frailty become more important. A minimally invasive approach becomes even more critical in this older population to mitigate risk. The determination of risk is a clinical decision and judgement, which should also take into consideration patient perspectives, values, preferences, and quality of life.

View details for DOI 10.1016/j.jtcvs.2021.07.030

View details for PubMedID 34716030

View details for Web of Science ID 000673145403271

View details for DOI 10.1200/JCO.2021.39.15_suppl.8548

View details for Web of Science ID 000708120604262

View details for DOI 10.1016/j.ijrobp.2019.03.045

View details for Web of Science ID 000717463600013

View details for Web of Science ID 000641160600087

View details for Web of Science ID 000641160600046

View details for Web of Science ID 000641160600097

View details for Web of Science ID 000631349600016

View details for Web of Science ID 000631349600076

Abstract

PURPOSE: The differential response of normal and tumor tissues to ultra-high dose rate radiation (FLASH) has raised new hope for treating solid tumors but, to date, the mechanism remains elusive. One leading hypothesis is that FLASH radiochemically depletes oxygen from irradiated tissues faster than it is replenished through diffusion. The purpose of this study is to investigate these effects within hypoxic multicellular tumor spheroids, through simulations and experiments.MATERIALS AND METHODS: Physicobiological equations were derived to model (i) the diffusion and metabolism of oxygen within spheroids; (ii) its depletion through reactions involving radiation-induced radicals; and (iii) the increase in radioresistance of spheroids, modeled according to the classical oxygen enhancement ratio and linear-quadratic response. These predictions were then tested experimentally in A549 spheroids exposed to electron irradiation at conventional (0.075 Gy/s) or FLASH (90 Gy/s) dose rates. Clonogenic survival, cell viability, and spheroid growth were scored post-radiation. Clonogenic survival of two other cell lines was also investigated.RESULTS: The existence of a hypoxic core in unirradiated tumor spheroids is predicted by simulations and visualized by fluorescence microscopy. Upon FLASH irradiation, this hypoxic core transiently expands, engulfing a large number of well-oxygenated cells. In contrast, oxygen is steadily replenished during slower conventional irradiation. Experimentally, clonogenic survival was around 3-fold higher in FLASH-irradiated spheroid compared to conventional irradiation, but no significant difference was observed for well-oxygenated 2D-cultured cells. This differential survival is consistent with the predictions of the computational model. FLASH irradiation of spheroids resulted in a dose-modifying factor of around 1.3 for doses above 10 Gy.CONCLUSION: Tumor spheroids can be used as a model to study FLASH irradiation in vitro . The improved survival of tumor spheroids receiving FLASH radiation confirms that ultra-fast radiochemical oxygen depletion and its slow replenishment are critical components of the FLASH effect.

View details for DOI 10.1016/j.ijrobp.2021.01.050

View details for PubMedID 33545301

Abstract

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

View details for DOI 10.6004/jnccn.2021.0058

View details for PubMedID 34902832

View details for Web of Science ID 000610079600029

Abstract

In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.

View details for DOI 10.1016/j.jtho.2021.01.1628

View details for PubMedID 33588109

Abstract

Purpose:Radiation dose delivered to targets located near the upper-abdomen or in the thorax are significantly affected by respiratory-motion. Relatively large-margins are commonly added to compensate for this motion, limiting radiation-dose-escalation. Internal-surrogates of target motion, such as a radiofrequency (RF) tracking system, i.e. Calypso System, are used to overcome this challenge and improve normal-tissue sparing. RF tracking systems consist of implanting transponders in the vicinity of the tumor to be tracked using radiofrequency-waves. Unfortunately, although the manufacture provides a universal quality-assurance (QA) phantom, QA-phantoms specifically for lung-applications are limited, warranting the development of alternative solutions to fulfil the tests mandated by AAPM's TG142. Accordingly, our objective was to design and develop a motion-phantom to evaluate Calypso for lung-applications that allows the Calypso Beacons to move in different directions to better simulate true lung-motion.Methods and Materials:A Calypso lung QA-phantom was designed, and 3D-printed. The design consists of three independent arms where the transponders were attached. A pinpoint-chamber with a buildup-cap was also incorporated. A 4-axis robotic arm was programmed to drive the motion-phantom to mimic breathing. After acquiring a four-dimensional-computed-tomography (4DCT) scan of the motion-phantom, treatment-plans were generated and delivered on a Varian TrueBeam with Calypso capabilities. Stationary and gated-treatment plans were generated and delivered to determine the dosimetric difference between gated and non-gated treatments. Portal cine-images were acquired to determine the temporal-accuracy of delivery by calculating the difference between the observed versus expected transponders locations with the known speed of the transponders' motion.Results:Dosimetric accuracy is better than TG142 tolerance of 2%. Temporal accuracy is greater than, TG142 tolerance of 100ms for beam-on, but less than 100ms for beam-hold.Conclusions:The robotic QA-phantom designed and developed in this study provides an independent phantom for performing Calypso lung-QA for commissioning and acceptance testing of Calypso for lung treatments.

View details for DOI 10.1088/1361-6560/abebaa

View details for PubMedID 33657537

View details for Web of Science ID 000582521500355

View details for Web of Science ID 000582521500346

View details for Web of Science ID 000582521501276

View details for Web of Science ID 000582521502042

View details for DOI 10.1016/j.ygyno.2020.05.102

View details for Web of Science ID 000579556200210

View details for DOI 10.1158/1538-7445.AM2020-5351

View details for Web of Science ID 000590059306341

View details for DOI 10.1158/1538-7445.AM2020-5357

View details for Web of Science ID 000590059306346

View details for Web of Science ID 000546013300059

View details for Web of Science ID 000699864000563

Abstract

OBJECTIVE: Concern exists regarding surgery after thoracic radiation. We aimed to assess early results of anatomic resection following induction therapy with platinum-based chemotherapy and full-dose thoracic radiation for resectable N2+ stage IIIA non-small cell lung cancer.METHODS: Two prospective trials were recently conducted by NRG Oncology in patients with resectable N2+ stage IIIA non-small cell lung cancer with the primary end point of mediastinal node sterilization following concurrent full-dose chemoradiotherapy (Radiation Therapy Oncology Group trials 0229 and 0839). All surgeons demonstrated postinduction resection expertise. Induction consisted of weekly carboplatin (area under the curve, 2.0) and paclitaxel (50mg/m2) and concurrent thoracic radiation 60Gy (0839)/61.2Gy (0229) in 30 fractions. Patients in study 0839 were randomized 2:1 to weekly panitumumab+chemoradiotherapy or chemoradiotherapy alone during induction. Primary results were similar in all treatment arms and reported previously. Short-term surgical outcomes are reported here.RESULTS: One hundred twenty-six patients enrolled; 93 (74%) had anatomic resection, 77 underwent lobectomy, and 16 underwent extended resection. Microscopically margin-negative resections occurred in 85 (91%). Fourteen (15%) resections were attempted minimally invasively, including 2 converted without event. Grade 3 or 4 surgical adverse events were reported in 26 (28%), 30-day mortality in 4 (4%) and 90-day mortality in 5 (5%). Patients undergoing extended resection experienced similar rates of grade 3 or 4 adverse events (odds ratio, 0.95; 95% confidence interval, 0.42-3.8) but higher 30-day (1.3% vs 18.8%) (odds ratio, 17.54; 95% confidence interval, 1.75-181.8) and 90-day mortality (2.6% vs 18.8%) (odds ratio, 8.65; 95% confidence interval, 1.3-56.9).CONCLUSIONS: Lobectomy was performed safely following full-dose concurrent chemoradiotherapy in these multi-institutional prospective trials; however, increased mortality was noted with extended resections.

View details for DOI 10.1016/j.jtcvs.2020.03.171

View details for PubMedID 32798022

View details for Web of Science ID 000560368303348

View details for Web of Science ID 000560368303378

Abstract

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

View details for DOI 10.1038/s41586-020-2140-0

View details for PubMedID 32269342

Abstract

Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

View details for DOI 10.1038/s43018-019-0011-0

View details for PubMedID 34505064

View details for PubMedCentralID PMC8425388

Abstract

PURPOSE: Pediatric radiotherapy requires optimal immobilization that often necessitates daily anesthesia. To decrease anesthesia use, we implemented a novel XXX system which projects video onto a radiolucent screen within the child's line of vision to provide attentional diversion. We investigated its reduction on anesthesia use, payer charges, and treatment time, as well as its impact on radiation delivery.METHODS AND MATERIALS: A 6-year retrospective analysis was performed among children undergoing radiotherapy (n=224), 3 years before and 3 after introduction of XXX. The frequency of anesthesia use before and after XXX implementation, as well as radiotherapy treatment times were compared. The number of spared anesthesia treatments allowed for a charge to payer analysis. To document lack of surface dose perturbation by XXX, a phantom craniospinal treatment course was delivered both with and without XXX. Additionally, an ion chamber course was delivered to document changes to dose at depth.RESULTS: More children were able to avoid anesthesia use entirely in the post-XXX cohort, compared to the pre-XXX cohort (73.2% vs 63.4%, p=0.03) and fewer required anesthesia for each treatment (18.8% vs 33%; p = 0.03). XXX introduction reduced anesthesia use for all ages studied. Treatment time per session was reduced by 38% using XXX compared to anesthesia. There were 326 fewer anesthesia sessions delivered over three years after XXX was introduced, with an estimated savings of > $500,000. OSLDs revealed a small increase in dose of 0.8%-9.5% with XXX, while the use of a thermomolded face mask increased skin dose as much as 58%.CONCLUSIONS: XXX introduction decreased anesthesia use in children undergoing radiotherapy; more avoided anesthesia entirely, and fewer needed it for every treatment. This resulted in a reduction in treatment time, and savings of nearly $550,000 in approximately 3 years, with minimal perturbation of radiotherapy dose delivery.

View details for DOI 10.1016/j.prro.2019.12.009

View details for PubMedID 31935524

Abstract

Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC. Methods: This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model. Results: The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; P = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; P = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively (P = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively (P = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUVmax value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics). Conclusions: Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients.

View details for DOI 10.7150/thno.50565

View details for PubMedID 33052242

Abstract

We evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose60Gy) for locally advanced non-small cell lung cancer (NSCLC).We retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured theMTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.We identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC=0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P=0.004 and P=7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P=0.001).Per-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.

View details for DOI 10.1186/s13014-020-01546-y

View details for PubMedID 32429982

Abstract

As C-arm linac radiation therapy evolves toward faster, more efficient delivery, and more conformal dosimetry, treatments with increasingly complex couch motions are emerging. Monitoring the patient motion independently of the couch motion during non-coplanar, non-isocentric, or dynamic couch treatments is a key bottleneck to their clinical implementation. The goal of this study is to develop a prototype real-time monitoring system for unconventional beam trajectories to ensure a safe and accurate treatment delivery.An in-house algorithm was developed for tracking using a couch-mounted three-dimensional (3D) depth camera. The accuracy of patient motion detection on the couch was tested on a 3D printed phantom created from the body surface contour exported from the treatment planning system. The technique was evaluated against a commercial optical surface monitoring system with known phantom displacements of 3, 5, and 7mm in lateral, longitudinal, and vertical directions by placing a head phantom on a dynamic platform on the treatment couch. The stability of the monitoring system was evaluated during dynamic couch trajectories, at speeds between 10.6 and 65cm/min.The proposed monitoring system agreed with the ceiling mounted optical surface monitoring system in longitudinal, lateral, and vertical directions within 0.5mm. The uncertainty caused by couch vibration increased with couch speed but remained sub-millimeter for speeds up to 32cm/min. For couch speeds of 10.6, 32.2, and 65cm/min, the uncertainty ranges were 0.27- 0.73mm, 0.15-0.87mm, and 0.28-1.29mm, respectively.By mounting a 3D camera in the same frame-of-reference as the patient and eliminating dead spots, this proof of concept demonstrates real-time patient monitoring during couch motion. For treatments with non-coplanar beams, multiple isocenters, or dynamic couch motion, this provides additional safety without additional radiation dose and avoids some of the complexity and limitations of room mounted systems.

View details for DOI 10.1002/acm2.12842

View details for PubMedID 32107845

Abstract

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

View details for DOI 10.1158/2159-8290.CD-20-0282

View details for PubMedID 33071215

Abstract

The National Cancer Institute's Radiation Research Program in collaboration with the Radiosurgery Society hosted a workshop on Understanding High-Dose, Ultra-High Dose rate and Spatially Fractionated Radiotherapy on August 20-21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically-based clinical trials.

View details for DOI 10.1016/j.ijrobp.2020.03.028

View details for PubMedID 32298811

Abstract

Radiation therapy benefits the majority of patients across the spectrum of cancer types. However, both local and distant tumor recurrences limit its clinical success. While departing from the established tenet of fractionation in clinical radiotherapy, ablative-intensity hypofractionated radiotherapy, especially stereotactic radiosurgery and stereotactic ablative radiotherapy, has emerged as an alternative paradigm achieving unprecedented rates of local tumor control. Direct tumor cell killing has been assumed to be the primary therapeutic mode of action of such ablative radiation. But with increasing recognition that tumor responses also depend on the immunostimulatory or immunosuppressive status of the tumor microenvironment, the immunologic effect of ablative radiotherapy is emerging as a key contributor to antitumor response. More recently, novel radiation modalities, such as spatially fractionated radiotherapy and ultrahigh dose rate FLASH irradiation, that venture even further from conventional paradigms have shown promise of increasing the therapeutic index of radiation therapy with the potential of immunomodulation. Here, we review the immunomodulatory impact of novel radiation therapy paradigms, heretofore considered radiobiological heresies, a deeper understanding of which is imperative to realizing fully their potential for more curative cancer therapy.

View details for DOI 10.1016/j.semradonc.2019.12.006

View details for PubMedID 32381299

View details for DOI 10.1038/s43018-019-0011-0

Abstract

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

View details for DOI 10.6004/jnccn.2019.0059

View details for Web of Science ID 000500944300007

View details for PubMedID 31805526

Abstract

Non-small-cell lung cancer (NSCLC) represents approximately 80-85% of lung cancer diagnoses and is the leading cause of cancer-related death worldwide. Recent studies indicate that image-based radiomics features from positron emission tomography/computed tomography (PET/CT) images have predictive power for NSCLC outcomes. To this end, easily calculated functional features such as the maximum and the mean of standard uptake value (SUV) and total lesion glycolysis (TLG) are most commonly used for NSCLC prognostication, but their prognostic value remains controversial. Meanwhile, convolutional neural networks (CNN) are rapidly emerging as a new method for cancer image analysis, with significantly enhanced predictive power compared to hand-crafted radiomics features. Here we show that CNNs trained to perform the tumor segmentation task, with no other information than physician contours, identify a rich set of survival-related image features with remarkable prognostic value. In a retrospective study on pre-treatment PET-CT images of 96 NSCLC patients before stereotactic-body radiotherapy (SBRT), we found that the CNN segmentation algorithm (U-Net) trained for tumor segmentation in PET and CT images, contained features having strong correlation with 2- and 5-year overall and disease-specific survivals. The U-Net algorithm has not seen any other clinical information (e.g. survival, age, smoking history, etc.) than the images and the corresponding tumor contours provided by physicians. In addition, we observed the same trend by validating the U-Net features against anextramural data set provided by Stanford Cancer Institute. Furthermore, through visualization of the U-Net, we also found convincing evidence that the regions of metastasis and recurrence appear to match with the regions where the U-Net features identified patterns that predicted higher likelihoods of death. We anticipate our findings will be a starting point for more sophisticated non-intrusive patient specific cancer prognosis determination. For example, the deep learned PET/CT features can not only predict survival but also visualize high-risk regions within or adjacent to the primary tumor and hence potentially impact therapeutic outcomes by optimal selection of therapeutic strategy or first-line therapy adjustment.

View details for DOI 10.1038/s41598-019-53461-2

View details for PubMedID 31754135

View details for Web of Science ID 000497337700109

View details for Web of Science ID 000492162203144

View details for DOI 10.1016/j.ijrobp.2019.06.610

View details for Web of Science ID 000485671502643

View details for DOI 10.1016/j.prro.2019.03.007

View details for Web of Science ID 000483978300015

View details for DOI 10.1016/j.ijrobp.2019.06.1137

View details for Web of Science ID 000485671501699

View details for DOI 10.1016/j.ijrobp.2019.06.2134

View details for Web of Science ID 000485671500365

View details for DOI 10.1016/j.ijrobp.2019.06.151

View details for Web of Science ID 000485671503008

View details for DOI 10.1016/j.ijrobp.2019.06.2430

View details for Web of Science ID 000485671501498

View details for DOI 10.1016/j.ijrobp.2019.06.1407

View details for Web of Science ID 000485671501426

View details for DOI 10.1001/jamaoncol.2019.1448

View details for PubMedID 31294751

View details for Web of Science ID 000471277703001

View details for DOI 10.1002/cam4.2172

View details for Web of Science ID 000474292100054

Abstract

Differentiating local recurrence from post-treatment changes on PET scans following stereotactic ablative radiotherapy (SABR) or hyperfractionation for lung tumors is challenging. We performed a prospective pilot study of 3-deoxy-3-[18F]-fluorothymidine (FLT)-PET-CT in patients with equivocal post-radiation FDG-PET-CT to assess disease recurrence. Methods: We prospectively enrolled 10 patients, 9 treated with SABR and 1 with hyperfractionated external beam radiotherapy for thoracic malignancy with subsequent equivocal follow-up FDG-PET-CT, to undergo FLT-PET-CT prior to biopsy or serial imaging. FLT-PET scans were interpreted by a radiologist with experience in reading FLT-PET-CT and blinded to the results of any subsequent biopsy or imaging. Results: Of the 10 patients enrolled, 8 were evaluable after FLT-PET-CT. Based on the FLT-PET-CT, a blinded radiologist accurately predicted disease recurrence vs. inflammatory changes in 7 patients (87.5%). The combination of higher lesion SUVmax and higher ratio of lesion SUVmax to SUVmax of mediastinal blood pool was indicative of recurrence. Qualitative assessment of increased degree of focality of the lesion also appears to be indicative of disease recurrence. Conclusion: Adjunctive FLT-PET-CT imaging can complement FDG-PET-CT scan in distinguishing post-treatment radiation changes from disease recurrence in thoracic malignancies. These findings support the investigation of FLT-PET-CT in a larger prospective study.

View details for DOI 10.3389/fonc.2019.00467

View details for PubMedID 31214507

View details for PubMedCentralID PMC6555304

View details for DOI 10.1200/JCO.2019.37.15_suppl.3092

View details for Web of Science ID 000487345805026

View details for DOI 10.1200/JCO.2019.37.15_suppl.2547

View details for Web of Science ID 000487345804497

View details for DOI 10.1016/S0140-6736(19)30278-8

View details for Web of Science ID 000468112000006

Abstract

Lung cancer as a second primary malignancy (lung-2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall and cancer-specific survival of patients diagnosed with lung-2 compared to lung-1. Primary lung cancer patients diagnosed from 1988 to 2014 in the Surveillance, Epidemiology, and End Results (SEER) program were included. Lung-2 was identified in patients with a previous diagnosis of nonlung primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer-specific mortality were estimated among patients with lung-2 compared to lung-1, adjusting for age and calendar period at diagnosis, sex, race, socioeconomic status, tumor stage, histology, tumor grade, and treatment. A total of 679541 and 85758 patients were identified as lung-1 and lung-2, respectively. Compared to lung-1, patients with lung-2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung-2 patients were at lower risk of lung cancer-specific mortality in the first 5years (HR, 0.77; 95% CI, 0.76-0.78 at <1year; HR, 0.87; 95% CI, 0.86-0.89 from 1 to <5years) but at higher risk thereafter (HR, 1.32; 95% CI, 1.27-1.37 from 5 to 10years), independent of tumor characteristics and cancer treatment. Similar pattern was found for overall mortality, although the survival benefit was restricted to the first year after diagnosis. Patients diagnosed with lung-2 face a favorable lung cancer-specific survival within the early period after diagnosis. A conservative approach to manage lung-2 solely based on malignancy history is not supported.

View details for PubMedID 30993899

View details for PubMedID 30999000

Abstract

PURPOSE: Numerous dose and fractionation schedules have been used to treat medically inoperable stage I Non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR). We evaluated published experiences with SBRT to determine local control (LC) rates as a function of SBRT dose.METHODS: One hundred sixty published articles reporting LC rates following SBRT for stage I NSCLC were identified. Quality of the series was assessed by evaluating the number of patients in the study, homogeneity of the dose regimen, length of follow-up time, and reporting of LC. Clinical data including 1, 2, 3, and 5 year tumor control probabilities for T1, T2, and combined T1 and T2 stage as a function of the biological effective dose were fitted to the linear quadratic (LQ), Universal survival curve (USC), and regrowth models.RESULTS: Forty-six studies met inclusion criteria. As measured by the goodness of fit chi2/ndf, with ndf as the number of degrees of freedom, none of the models were ideal fits for the data. Of the three models, the regrowth model provides the best fit to the clinical data. For the regrowth model, the fitting yielded an alpha/beta ratio of approximately 25 Gy for T1 tumors, 19 Gy for T2 tumors, and 21 Gy for T1 and T2 combined. In order to achieve the maximal LC rate, the predicted physical dose schemes when prescribed at the periphery of the planning target volume (PTV) are 43 +/- 1 Gy in 3 fractions, 47 +/- 1 Gy in 4 fractions, and 50 +/- 1 Gy in 5 fractions for combined T1 and T2 tumors.CONCLUSION: Early stage NSCLC is radioresponsive when treated with SBRT/SABR. A steep dose-response relationship exists with high rates of durable LC when physical doses of 43-50 Gy are delivered in 3-5 fractions.

View details for PubMedID 30954520

Abstract

Purpose: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR).Methods and Materials: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort.Results: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P=.10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P=.07). MTGR greater than 0.04mL/d was prognostic of decreased survival in discovery (P=.048) and validation cohorts (P<.01).Conclusions: MTGR greater than 0.04mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

View details for PubMedID 31011689

View details for DOI 10.1016/j.adro.2018.11.006

View details for Web of Science ID 000516858500027

Abstract

Stereotactic ablative radiotherapy (SABR) has emerged as a standard-of-care treatment for patients with early stage non-small cell lung cancer (NSCLC) who are poor surgical candidates. Current evidence supports the consensus that lung SABR with BED 100 Gy leads to high local tumor control, and that the treatment is generally well-tolerated when applied to peripheral lung tumors. However, several studies present conflicting evidence for the treatment of central and ultra-central lung tumors, with some showing superb outcomes and others showing concerning rates of morbidity and mortality. Therefore, treatment of central and especially ultra-central lung tumors with SABR remains controversial. In this review, we aim to present the existing evidence for SABR treatment of central and ultra-central lung tumors and delineate the factors that could lead to significant toxicity.

View details for DOI 10.21037/tro.2019.05.01

View details for PubMedID 33880444

View details for PubMedCentralID PMC8054989

View details for DOI 10.1016/j.prro.2019.09.011

View details for PubMedID 31574319

View details for DOI 10.1259/bjr.20180228

View details for Web of Science ID 000456614000006

Abstract

Stereotactic ablative radiotherapy (SABR) is highly effective at controlling early stage primary lung cancer and lung metastases. Although previous studies have suggested that treating multiple lung tumors with SABR is safe, post-treatment changes in respiratory function have not been analyzed in detail.We retrospectively identified patients with 2 or more primary lung cancers or lung metastases treated with SABR and analyzed clinical outcomes and predictors of toxicity. We defined a composite respiratory decline endpoint to include increased oxygen requirement, increased dyspnea scale, or death from respiratory failure not owing to disease progression.A total of 86 patients treated with SABR to 203 lung tumors were analyzed. A total of 21.8% and 41.8% of patients developed composite respiratory decline at 2 and 4 years, respectively. When accounting for intrathoracic disease progression, 12.7% of patients developed composite respiratory decline at 2 years. Of the patients, 7.9% experienced grade 2 or greater radiation pneumonitis. No patient- or treatment-related factor predicted development of respiratory decline. The median overall survival was 46.9 months, and the median progression-free survival was 14.8 months. The cumulative incidence of local failure was 9.7% at 2 years.Although our results confirm that SABR is an effective treatment modality for patients with multiple lung tumors, we observed a high rate of respiratory decline after treatment, which may be owing to a combination of treatment and disease effects. Future studies may help to determine ways to avoid pulmonary toxicity from SABR.

View details for DOI 10.1016/j.cllc.2019.05.015

View details for PubMedID 31377143

View details for Web of Science ID 000505772704094

Abstract

OBJECTIVE:: Stereotactic ablative radiotherapy (SABR) is being increasingly used as a non-invasive treatment for early-stage non-small cell lung cancer (NSCLC). A non-invasive method to estimate treatment outcomes in these patients would be valuable, especially since access to tissue specimens is often difficult in these cases.METHODS:: We developed a method to predict survival following SABR in NSCLC patients using analysis of quantitative image features on pre-treatment CT images. We developed a Cox Lasso model based on two-dimensional Riesz wavelet quantitative texture features on CT scans with the goal of separating patients based on survival.RESULTS:: The median log-rank p-value for 1000 cross-validations was 0.030. Our model was able to separate patients based upon predicted survival. When we added tumor size into the model, the p-value lost its significance, demonstrating that tumor size is not a key feature in the model but rather decreases significance likely due to the relatively small number of events in the dataset. Furthermore, running the model using Riesz features extracted either from the solid component of the tumor or from the ground glass opacity (GGO) component of the tumor maintained statistical significance. However, the p-value improved when combining features from the solid and the GGO components, demonstrating that there are important data that can be extracted from the entire tumor.CONCLUSIONS:: The model predicting patient survival following SABR in NSCLC may be useful in future studies by enabling prediction of survival-based outcomes using radiomics features in CT images.ADVANCES IN KNOWLEDGE:: Quantitative image features from NSCLC nodules on CT images have been found to significantly separate patient populations based on overall survival (p = 0.04). In the long term, a non-invasive method to estimate treatment outcomes in patients undergoing SABR would be valuable, especially since access to tissue specimens is often difficult in these cases.

View details for PubMedID 30457885

View details for DOI 10.1016/j.ijrobp.2018.01.006

View details for Web of Science ID 000447789700056

View details for DOI 10.1016/j.ijrobp.2018.03.045

View details for Web of Science ID 000447789700063

View details for DOI 10.1016/j.ijrobp.2018.07.1826

View details for Web of Science ID 000447811602078

View details for DOI 10.1016/j.ijrobp.2018.07.1890

View details for Web of Science ID 000447811602141

View details for DOI 10.1016/j.ijrobp.2018.07.1802

View details for Web of Science ID 000447811602055

View details for DOI 10.1016/j.ijrobp.2018.07.1820

View details for Web of Science ID 000447811602073

View details for DOI 10.1016/j.ijrobp.2018.07.1856

View details for Web of Science ID 000447811602108

View details for DOI 10.1016/j.lungcan.2018.07.033

View details for Web of Science ID 000448100600012

Abstract

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

View details for DOI 10.6004/jnccn.2018.0079

View details for PubMedID 30323087

View details for DOI 10.1016/j.jtho.2018.08.169

View details for Web of Science ID 000454014500156

Abstract

INTRODUCTION: Invasive nodal evaluation (INE) is used to improve staging for early stage non-small cell lung cancer (NSCLC), including when stereotactic ablative radiation (SABR) is used. Consensus guidelines from the NCCN recommend performing INE for patients with T2N0 tumors and considering INE for those with T1N0 tumors. We reasoned that if INE results in significant stage migration in the form of substantially fewer patients with occult nodal involvement, then patients treated with SABR who do not undergo INE should have worse overall survival (OS).METHODS: Patients diagnosed 2004-2014 with stage T1-2N0M0 NSCLC and treated with SABR were identified from the National Cancer Database. Factors associated with INE were determined using mixed effects logistic regression. We tested for an association between INE and OS for patients diagnosed 2004-2013 using mixed effects proportional hazards regression methods.RESULTS: 24,603 SABR patients were identified. 6% of the 19,322 patients with T1 tumors and 9% of the 5281 patients with T2 tumors had INE. Median OS was 2.8 years for the no-INE group and 2.7 years for the INE group (log-rank P=0.69). No significant association was observed between the use of INE and OS in the univariate analysis (HR 1.02, 95% CI 0.94-1.11) or the multivariate analysis (HR 0.94, 95% CI 0.86-1.02). These findings were confirmed using propensity score matched and instrumental variable analysis. On subgroup analysis, INE was associated with a non-significant trend for improved OS in patients with T2 tumors (HR 0.87, 95% CI 0.76-1.00) but not T1 tumors (HR 0.98, 95% CI 0.88-1.09).CONCLUSIONS: Despite current NCCN recommendations, the rate of INE was low for patients with stage T1 or T2 tumors. While omitting INE represents a compromise in the completeness of nodal evaluation, we found that it was not associated with a detriment in overall survival.

View details for PubMedID 30268484

Abstract

Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear.To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection.Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014.The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks.Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points.Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively.As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer.ClinicalTrials.gov Identifier: NCT00551369.

View details for PubMedID 29852037

View details for PubMedCentralID PMC6117102

View details for DOI 10.1016/j.radonc.2018.05.025

View details for Web of Science ID 000444505600001

View details for PubMedID 29921460

View details for DOI 10.1016/j.cllc.2018.04.003

View details for Web of Science ID 000442538700007

Abstract

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

View details for DOI 10.6004/jnccn.2018.0062

View details for PubMedID 30006423

View details for DOI 10.1016/j.prro.2017.12.005

View details for Web of Science ID 000436836900004

View details for Web of Science ID 000434978000025

View details for Web of Science ID 000432447200003

View details for Web of Science ID 000437723401179

Abstract

Imaging after stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer can detect recurrences and second primary lung cancers; however, the optimal follow-up practice of these patients remains unclear. We sought to establish consensus recommendations for surveillance after SABR.International opinion leaders in thoracic radiation oncology and radiology were invited to participate (n = 31), with 11 accepting (9 radiation oncologists, 2 radiologists). Consensus-building was achieved using a 3-round Delphi process. Participants rated their agreement/disagreement with statements using a 5-point Likert scale. An a priori threshold of 75% agreement/disagreement was required for consensus.A 100% response rate was achieved and final consensus statements were approved by all participants. The consensus statements were: (1.1) thoracic computed tomography (CT) scans should be ordered routinely in follow-up; (1.2) if there is a suspicion for local recurrence (LR), fludeoxyglucose positron emission tomography/CT scans are strongly recommended. Otherwise, there is limited evidence to guide routine use of fludeoxyglucose positron emission tomography /CT; (1.3) CT imaging is not recommended at 6 weeks, but is recommended at months 3, 6, and 12 in year 1 and then every 6 months in year 2 and annually in years 3 through 5; (1.4) after 5 years, CT imaging should continue, although no consensus was reached regarding the frequency. (2.1) Response Evaluation Criteria in Solid Tumors 1.1 criteria are not sufficient for detecting LR; (2.2) a formal scoring system, informed by validated data, should be used to classify high-risk imaging features predictive of LR; (2.3) CT findings suspicious for LR include: infiltration into adjacent structures, bulging margins, sustained growth, mass-like growth, spherical growth, craniocaudal growth, and loss of air bronchograms. (3) Salvage therapy without pathologic confirmation of recurrence is acceptable if imaging findings are highly suspicious and a biopsy is not safe/feasible or if an attempted biopsy was nondiagnostic.These guidelines provide international expert consensus on areas of uncertainty in the management of early-stage non-small cell lung cancer patients after SABR.

View details for PubMedID 29291965

Abstract

Prognostic biomarkers are needed to guide the management of early-stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.We retrospectively analyzed data of stage I NSCLC in 8 cohorts.On the basis of an analysis of 39 computed tomography (CT) features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n=117) and tested it in an external cohort (n=88).A third cohort of 89 patients with CT and gene expression data was used to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from 5 gene expression cohorts (n=639) and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.An imaging signature consisting of a pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (P=.0005 and P=.0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate<0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival when we adjusted for known prognostic factors (hazard ratio, 1.81; 95% confidence interval, 1.34-2.44; P<.0001) and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (P<.01) regarding concordance index (0.70 vs 0.62-0.63).The proposed CT imaging signature reflects fundamental biological differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.

View details for PubMedID 29439884

View details for DOI 10.1177/1533034617749419

View details for Web of Science ID 000429305700016

Abstract

PURPOSE: The deformable registration of pulmonary computed tomography images before and after radiation therapy is challenging due to anatomic changes from radiation fibrosis. We hypothesize that a line-enhanced registration algorithm can reduce landmark error over the entire lung, including the irradiated regions, when compared to an intensity-based deformable registration algorithm.MATERIALS: Two intensity-based B-spline deformable registration algorithms of pre-radiation therapy and post-radiation therapy images were compared. The first was a control intensity-based algorithm that utilized computed tomography images without modification. The second was a line enhancement algorithm that incorporated a Hessian-based line enhancement filter prior to deformable image registration. Registrations were evaluated based on the landmark error between user-identified landmark pairs and the overlap ratio.RESULTS: Twenty-one patients with pre-radiation therapy and post-radiation therapy scans were included. The median time interval between scans was 1.2 years (range: 0.3-3.3 years). Median landmark errors for the line enhancement algorithm were significantly lower than those for the control algorithm over the entire lung (1.67 vs 1.83 mm; P < .01), as well as within the 0 to 5 Gy (1.40 vs 1.57; P < .01) and >5 Gy (2.25 vs 3.31; P < .01) dose intervals. The median lung mask overlap ratio for the line enhancement algorithm (96.2%) was greater than that for the control algorithm (95.8%; P < .01). Landmark error within the >5 Gy dose interval demonstrated a significant inverse relationship with post-radiation therapy fibrosis enhancement after line enhancement filtration (Pearson correlation coefficient = -0.48; P = .03).CONCLUSION: The line enhancement registration algorithm is a promising method for registering images before and after radiation therapy.

View details for PubMedID 29343206

Abstract

Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P= .009 and P= .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P= .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

View details for PubMedID 29759331

Abstract

Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

View details for PubMedID 28830717

View details for PubMedID 28668669

View details for DOI 10.1016/j.jtho.2017.09.560

View details for Web of Science ID 000463860800456

View details for DOI 10.1016/j.ijrobp.2017.06.269

View details for Web of Science ID 000411559107060

View details for DOI 10.1016/j.ijrobp.2017.06.1756

View details for Web of Science ID 000411559104024

View details for DOI 10.1016/j.ijrobp.2017.06.1806

View details for Web of Science ID 000411559104073

View details for DOI 10.1016/j.ijrobp.2017.06.1695

View details for Web of Science ID 000411559103253

View details for DOI 10.1016/j.ijrobp.2017.06.122

View details for Web of Science ID 000411559106186

View details for Web of Science ID 000411559104135

View details for DOI 10.1016/j.ijrobp.2017.06.1957

View details for Web of Science ID 000411559104221

View details for DOI 10.1016/j.ijrobp.2017.06.544

View details for Web of Science ID 000411559108023

View details for DOI 10.1016/j.ijrobp.2017.06.061

View details for Web of Science ID 000411559106127

View details for DOI 10.1016/j.ijrobp.2017.06.021

View details for Web of Science ID 000411559106087

Abstract

Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung.

View details for DOI 10.1016/j.semradonc.2017.02.001

View details for PubMedID 28577827

Abstract

The rising incidence of early-stage lung cancer, particularly in medically inoperable patients, is anticipated because of the implementation of early detection strategies and population aging in the United States and worldwide. This mandates the development of noninvasive curative treatment approaches for this disease. Stereotactic ablative radiotherapy (SABR) has recently emerged as a standard of care for early-stage lung cancer in medically inoperable patients who cannot safely tolerate surgical lobectomy, the established standard for operable patients. Further experience has demonstrated key principles with this highly conformal and dose-intensive radiation technique, including the need for sufficiently high biologically effective dose to achieve optimal local control, dose-fractionation modifications needed to treat centrally located tumors safely, and individualization of treatment based on tumor size, location, and other factors. SABR requires particular technical expertise including a nuanced understanding of dose prescription and calculation and appropriate management of tumor and organ motion. Progress continues as increasing experience with and data on SABR in selected cohorts of medically operable patients suggest comparable oncologic outcomes and a more favorable toxicity profile that challenges the historical standard of care for broader patient populations.

View details for DOI 10.1016/j.semradonc.2017.03.001

View details for PubMedID 28577829

View details for Web of Science ID 000426452604155

View details for DOI 10.1016/j.ijrobp.2017.02.101

View details for Web of Science ID 000403079100049

Abstract

In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach.Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged 65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach.1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide.Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.

View details for PubMedID 28625632

View details for Web of Science ID 000426452601080

Abstract

To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (/=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (FEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse FEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved FEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing FEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.

View details for DOI 10.1016/j.radonc.2017.03.021

View details for PubMedID 28460826

View details for Web of Science ID 000404949900118

Abstract

Radiation therapy plays an important role in the management of both limited stage and extensive stage small cell lung cancer. For limited stage disease, there has been a trend toward reduced size of thoracic radiation fields, which has the potential to reduce toxicity. FDG-PET staging helps make this possible by more accurately identifying areas of nodal and metastatic involvement. Trials have demonstrated similar outcomes using a range of radiation fractionation schedules, allowing flexibility in individualizing treatment. Using advanced radiation therapy techniques such as intensity-modulated radiation therapy, it may be possible to deliver fewer, higher dose fractions and achieve similar results to the hyperfractionated regimen. For extensive stage disease, consolidative thoracic radiation therapy after chemotherapy was recently shown to improve overall survival in certain patient subsets. Prophylactic cranial irradiation continues to play an important role in management of all stages of small cell lung cancer. Debate continues about the neurocognitive effects of this treatment, and whether MRI surveillance is an acceptable alternative. Strategies such as hippocampal avoidance may reduce the cognitive effects of prophylactic cranial irradiation in the future. Finally, in the last few years stereotactic ablative radiation therapy followed by chemotherapy has emerged as a promising treatment for stage I small cell lung cancer. This radiation treatment is usually given over 1-5 fractions and appears to provide a good rate of local control with a low rate of serious toxicity.

View details for DOI 10.1007/s11864-017-0467-z

View details for PubMedID 28391424

Abstract

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

View details for Web of Science ID 000399398700009

View details for PubMedID 28404761

View details for Web of Science ID 000443300500123

Abstract

This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square ((2)) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large / ratios of about 20Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1Gy physical dose at isocenters per fraction (5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large / ratios of about 20Gy. The six models predict that a BED (calculated with / of 20) of 90Gy is sufficient to achieve TCP95%. Among the models considered, the regrowth model leads to a better fit to the clinical data.

View details for DOI 10.1016/j.radonc.2016.11.006

View details for PubMedID 27871671

Abstract

Radiation therapy is an important component of treatment for many childhood cancers. Depending upon the age and maturity of the child, pediatric radiation therapy often requires general anesthesia for immobilization, position reproducibility, and daily treatment delivery. We designed and clinically implemented a radiation therapy-compatible audiovisual system that allows children to watch streaming video during treatment, with the goal of reducing the need for daily anesthesia through immersion in video.We designed an audiovisual-assisted therapeutic ambience in radiation therapy (AVATAR) system using a digital media player with wireless streaming and pico projector, and a radiolucent display screen positioned within the child's field of view to him or her with sufficient entertainment and distraction for the duration of serial treatments without the need for daily anesthesia. We piloted this system in 25 pediatric patients between the ages of 3 and 12 years. We calculated the number of fractions of radiation for which this system was used successfully and anesthesia avoided and compared it with the anesthesia rates reported in the literature for children of this age.Twenty-three of 25 patients (92%) were able to complete the prescribed course of radiation therapy without anesthesia using the AVATAR system, with a total of 441 fractions of treatment administered when using AVATAR. The median age of patients successfully treated with this approach was 6 years. Seven of the 23 patients were initially treated with daily anesthesia and were successfully transitioned to use of the AVATAR system. Patients and families reported an improved treatment experience with the use of the AVATAR system compared with anesthesia.The AVATAR system enables a high proportion of children to undergo radiation therapy without anesthesia compared with reported anesthesia rates, justifying continued development and clinical investigation of this technique.

View details for DOI 10.1016/j.prro.2017.01.007

View details for PubMedID 28242188

View details for Web of Science ID 000400372500266

View details for Web of Science ID 000413055801024

Abstract

Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR.We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR.Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity.While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.

View details for PubMedID 28669706

View details for Web of Science ID 000426664301528

Abstract

Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

View details for PubMedID 28899864

Abstract

To evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC).We retrospectively analysed seven NSCLC cohorts. A quantitative PCI was defined on CT as the length of tumour-pleura interface normalised by tumour diameter. We evaluated the prognostic value of PCI in a discovery cohort (n=117) and tested in an external cohort (n=88) of stage I NSCLC. Additionally, we identified the molecular correlates and built a gene expression-based surrogate of PCI using another cohort of 89 patients. To further evaluate the prognostic relevance, we used four datasets totalling 775 stage I patients with publically available gene expression data and linked survival information.At a cutoff of 0.8, PCI stratified patients for overall survival in both imaging cohorts (log-rank p=0.0076, 0.0304). Extracellular matrix (ECM) remodelling was enriched among genes associated with PCI (p=0.0003). The genomic surrogate of PCI remained an independent predictor of overall survival in the gene expression cohorts (hazard ratio: 1.46, p=0.0007) adjusting for age, gender, and tumour stage.CT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC. A quantitative pleural contact index (PCI) predicts survival in early stage NSCLC. PCI is associated with extracellular matrix organisation and collagen catabolic process. A multi-gene surrogate of PCI is an independent predictor of survival. PCI can be used to noninvasively identify patients with poor prognosis.

View details for PubMedID 28786009

Abstract

Stereotactic ablative radiation therapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using noncoplanar volumetric modulated arc radiation therapy (VMAT) to reduce chest wall dose from lung SABR.Twenty lung SABR VMAT plans in which the chest wall volume receiving 30 Gy or higher (V30) exceeded 30 mL were replanned by noncoplanar VMAT with opposite 15 couch kicks. Dosimetric parameters including chest wall V30 and V40; lung V5, V10, V20, and mean dose; Paddick high-dose conformity index; intermediate-dose conformity index; and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t test was used to evaluate the difference of the dosimetric parameters between coplanar 1 arc (cVMAT1), coplanar 2 arcs (cVMAT2), and noncoplanar two arcs (nVMAT2) plans; differences with P < .05 were considered statistically significant.V30 and V40 for chest wall were reduced on average by 20% 9% and 15% 11% (mean standard deviation) from cVMAT2 plans to nVMAT2 plans (P < .01 for both comparisons) and by 8% 7% and 16% 13% from cVMAT1 plans to cVMAT2 plans (P < .003 for both comparisons). The differences in lung mean dose were <0.2 Gy among cVMAT1, cVMAT2, and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared with cVMAT2. The Paddick high-dose conformity indexes were 0.88 0.03, 0.89 0.04, and 0.91 0.03, and intermediate-dose conformity indexes were 3.88 0.49, 3.80 0.44 and 3.51 0.38 for cVMAT1, cVMAT2, and nVMAT2, respectively.We found that noncoplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.

View details for PubMedID 29452868

Abstract

Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. 2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

View details for DOI 10.1158/2159-8290.CD-16-0127

View details for Web of Science ID 000396017700024

View details for PubMedCentralID PMC5222718

Abstract

This paper proposes a novel imaging biomarker of lung cancer relapse from 3-D texture analysis of CT images. Three-dimensional morphological nodular tissue properties are described in terms of 3-D Riesz-wavelets. The responses of the latter are aggregated within nodular regions by means of feature covariances, which leverage rich intra- and inter- variations of the feature space dimensions. When compared to the classical use of the average for feature aggregation, feature covariances preserve spatial co-variations between features. The obtained Riesz-covariance descriptors lie on a manifold governed by Riemannian geometry allowing geodesic measurements and differentiations. The latter property is incorporated both into a kernel for support vector machines (SVM) and a manifold-aware sparse regularized classifier. The effectiveness of the presented models is evaluated on a dataset of 110 patients with non-small cell lung carcinoma (NSCLC) and cancer recurrence information. Disease recurrence within a timeframe of 12 months could be predicted with an accuracy of 81.3-82.7%. The anatomical location of recurrence could be discriminated between local, regional and distant failure with an accuracy of 78.3-93.3%. The obtained results open novel research perspectives by revealing the importance of the nodular regions used to build the predictive models.

View details for DOI 10.1109/TMI.2016.2591921

View details for Web of Science ID 000391547700011

View details for PubMedID 27429433

Abstract

Alternative treatment regimens are needed for patients with non-small cell lung cancer (NSCLC) who cannot receive definitive treatment with concurrent chemoradiotherapy, surgery, or stereotactic ablative radiotherapy (SABR).We report survival, patterns of failure and toxicity outcomes for patients with NSCLC who were not eligible for surgical resection, concurrent chemoradiotherapy, or SABR and underwent hypofractionated intensity-modulated radiotherapy (IMRT). Kaplan-Meier survival analysis was used to evaluate the progression-free and overall survival. Competing risk analysis was used to evaluate in-field, locoregional, and distant failure.A total of 42 patients treated to 52.5 to 60 Gy in 15 fractions were included. Most of the patients had metastatic or recurrent disease (64%) and a relatively large, centrally located tumor burden (74%). The median follow-up period was 13 months (interquartile range, 6-18 months). All patients received the total prescribed dose. The median survival was 15.1 months. The overall and progression-free survival rates at 1 year were 63% and 22.5%, respectively. The pattern of failure was predominantly distant, with only 2% of patients experiencing isolated in-field recurrence. The cumulative incidence of in-field failure at 6 and 12 months was 2.5% (95% confidence interval, 0.4%-15.6%) and 16.1% (95% confidence interval, 7.5%-34.7%), respectively. The risk of esophageal toxicity was associated with the esophageal mean dose, maximal point dose, and dose to the 5 cm(3) volume. The risk of pneumonitis was associated with the lung mean dose and volume receiving 18 Gy.Hypofractionated IMRT without concurrent chemotherapy provides favorable rates of local control and survival for well-selected patients with NSCLC who cannot tolerate standard definitive therapy.

View details for DOI 10.1016/j.cllc.2016.05.024

View details for PubMedID 27378172

Abstract

Prognostic metabolic imaging indices are needed for risk stratification for patients with locally advanced oropharyngeal cancer.We retrospectively examined pretreatment and midtreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) parameters in patients with locally advanced oropharyngeal cancer who were treated with definitive chemoradiation.A total of 74 patients were evaluated. Pretreatment metabolic tumor volume (MTV) using threshold of 50% standardized uptake value (SUV) maximum (MTV50% ) was associated with progression-free survival (PFS; p = .003; hazard ratio [HR] = 1.57 per 10 cc; 95% confidence interval [CI] = 1.17-2.11) and overall survival (OS; p = .01; HR = 1.36 per 10 cc; 95% CI = 1.07-1.74). Midtreatment MTV using a threshold of SUV 2.0 (MTV2.0 ) was associated with PFS (p < .001; HR = 1.24 per 10 cc; 95% CI = 1.10-1.39) and OS (p = .009; HR = 1.21 per 10 cc; 95% CI = 1.05-1.39). Nodal total lesion glycolysis (TLG) velocity >5% decrease/week was associated with improved PFS (p = .04; HR = 0.37; 95% CI = 0.15-0.95).Metabolic response during chemoradiation is associated with survival in locally advanced oropharyngeal cancer and may aid with risk-adapting treatment. 2016 Wiley Periodicals, Inc. Head Neck, 2016.

View details for DOI 10.1002/hed.24454

View details for PubMedID 27043927

View details for DOI 10.1016/j.ijrobp.2016.06.1692

View details for Web of Science ID 000387655803354

View details for DOI 10.1016/j.ijrobp.2016.06.112

View details for Web of Science ID 000387655804429

View details for DOI 10.1016/j.ijrobp.2016.06.2330

View details for Web of Science ID 000387655804245

View details for DOI 10.1016/j.ijrobp.2016.06.1100

View details for Web of Science ID 000387655802495

View details for DOI 10.1016/j.ijrobp.2016.06.1776

View details for Web of Science ID 000387655803435

View details for Web of Science ID 000387655804563

Abstract

Purpose To identify quantitative imaging biomarkers at fluorine 18 ((18)F) positron emission tomography (PET) for predicting distant metastasis in patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods In this institutional review board-approved HIPAA-compliant retrospective study, the pretreatment (18)F fluorodeoxyglucose PET images in 101 patients treated with stereotactic ablative radiation therapy from 2005 to 2013 were analyzed. Data for 70 patients who were treated before 2011 were used for discovery purposes, while data from the remaining 31 patients were used for independent validation. Quantitative PET imaging characteristics including statistical, histogram-related, morphologic, and texture features were analyzed, from which 35 nonredundant and robust features were further evaluated. Cox proportional hazards regression model coupled with the least absolute shrinkage and selection operator was used to predict distant metastasis. Whether histologic type provided complementary value to imaging by combining both in a single prognostic model was also assessed. Results The optimal prognostic model included two image features that allowed quantification of intratumor heterogeneity and peak standardized uptake value. In the independent validation cohort, this model showed a concordance index of 0.71, which was higher than those of the maximum standardized uptake value and tumor volume, with concordance indexes of 0.67 and 0.64, respectively. The prognostic model also allowed separation of groups with low and high risk for developing distant metastasis (hazard ratio, 4.8; P = .0498, log-rank test), which compared favorably with maximum standardized uptake value and tumor volume (hazard ratio, 1.5 and 2.0, respectively; P = .73 and 0.54, log-rank test, respectively). When combined with histologic types, the prognostic power was further improved (hazard ratio, 6.9; P = .0289, log-rank test; and concordance index, 0.80). Conclusion PET imaging characteristics associated with distant metastasis that could potentially help practitioners to tailor appropriate therapy for individual patients with early-stage NSCLC were identified. () RSNA, 2016 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.2016151829

View details for PubMedID 27046074

Abstract

The impact of audiovisual (AV) biofeedback on four dimensional (4D) positron emission tomography (PET) and 4D computed tomography (CT) image quality was investigated in a prospective clinical trial (NCT01172041).4D-PET and 4D-CT images of ten lung cancer patients were acquired with AV biofeedback (AV) and free breathing (FB). The 4D-PET images were analyzed for motion artifacts by comparing 4D to 3D PET for gross tumor volumes (GTVPET) and maximum standardized uptake values (SUVmax). The 4D-CT images were analyzed for artifacts by comparing normalized cross correlation-based scores (NCCS) and quantifying a visual assessment score (VAS). A Wilcoxon signed-ranks test was used for statistical testing.The impact of AV biofeedback varied widely. Overall, the 3D to 4D decrease of GTVPET was 1.21.3cm(3) with AV and 0.61.8cm(3) for FB. The 4D-PET increase of SUVmax was 1.30.9 with AV and 1.30.8 for FB. The 4D-CT NCCS were 0.650.27 with AV and 0.600.32 for FB (p=0.08). The 4D-CT VAS was 0.02.7.This study demonstrated a high patient dependence on the use of AV biofeedback to reduce motion artifacts in 4D imaging. None of the hypotheses tested were statistically significant. Future development of AV biofeedback will focus on optimizing the human-computer interface and including patient training sessions for improved comprehension and compliance.

View details for DOI 10.1016/j.radonc.2016.05.016

View details for PubMedID 27256597

Abstract

To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP).Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05).We propose a robust intratumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful imaging biomarkers in many cancer types.

View details for DOI 10.1016/j.ijrobp.2016.03.018

View details for PubMedID 27212196

Abstract

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

View details for PubMedID 27407123

Abstract

To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p<0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV>0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV>0.56 or MLD>5.88Gy equivalent dose in 2Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p<0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV>0.56 and MLD>5.88Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

View details for DOI 10.1016/j.radonc.2016.05.007

View details for PubMedID 27267049

View details for DOI 10.1118/1.4955673

View details for PubMedID 28046308

View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500

View details for Web of Science ID 000404711506257

View details for DOI 10.1200/JCO.2016.34.15_suppl.8510

View details for Web of Science ID 000404711505242

Abstract

High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield 15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

View details for DOI 10.1038/nbt.3520

View details for PubMedID 27018799

View details for DOI 10.7759/cureus.578

View details for Web of Science ID 000453611400028

Abstract

We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation.We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2Gy per fraction equivalent dose (EQD2; /=2 for spinal cord; /=3 for other critical structures).We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16months (range: 1-71months) following initial RT. Median follow-up was 17months (range: 3-57months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Criticalstructures receiving 75Gy EQD2 included spinal cord (1cm(3); n=1), esophagus (1cm(3); n=10), trachea (1cm(3); n=11), heart (1cm(3); n=9), aorta (1cm(3); n=16), superior vena cava (1cm(3); n=12), brachial plexus (0.2cm(3); n=2), vagus nerve (0.2cm(3); n=7), sympathetic trunk (0.2cm(3); n=4), chest wall (30cm(3); n=12), and proximal bronchial tree (1cm(3); n=17). Cumulativedose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade 2 (n=3, D1 cm(3) range: 41.0-100.6Gy), chest wall grade 2 (n=4; D30cm(3) range: 35.0-117.2Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2cm(3) range: 207.5-302.2Gy), brachial plexopathy (n=1; D0.2cm(3)=242.5Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2cm(3)=130.8Gy). No grade 4 toxicity was observed.Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

View details for DOI 10.1016/j.ijrobp.2015.12.007

View details for PubMedID 26831903

Abstract

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

View details for PubMedID 26957612

Abstract

To investigate the hypothesis that CT ventilation functional image-based IMRT plans designed to avoid irradiating highly-functional lung regions are comparable to single-photon emission CT (SPECT) ventilation functional image-based plans.Three IMRT plans were created for eight thoracic cancer patients using: (1) CT ventilation functional images, (2) SPECT ventilation functional images, and (3) anatomic images (no functional images). CT ventilation images were created by deformable image registration of 4D-CT image data sets and quantitative analysis. The resulting plans were analyzed for the relationship between the deviations of CT-functional plan metrics from anatomic plan metrics (CT-anatomic) and those of SPECT-functional plans (SPECT-anatomic), and moreover for agreements of various metrics between the CT-functional and SPECT-functional plans.The relationship between CT-anatomic and SPECT-anatomic was strong (e.g., R=0.94; linear regression slope 0.71). The average differences and 95% limits of agreement between the CT-functional and SPECT-functional plan metrics (except for monitor units) for various structures were mostly less than 1% and 2%, respectively.This study demonstrated a reasonable agreement between the CT ventilation functional image-based IMRT plans and SPECT-functional plans, suggesting the potential for CT ventilation imaging to serve as a surrogate for SPECT ventilation in functional image-guided radiotherapy.

View details for DOI 10.1016/j.radonc.2016.02.019

View details for PubMedID 26922488

View details for DOI 10.7759/cureus.477

View details for Web of Science ID 000453610500005

Abstract

We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions (70 Gy equivalent dose in 2 Gy fractions). The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy.

View details for DOI 10.7759/cureus.578

View details for PubMedID 27226939

View details for DOI 10.1063/1.4965631

View details for Web of Science ID 000389510300042

Abstract

The first stereotactic arrhythmia radioablation (STAR) of ventricular tachycardia (VT) was delivered at Stanford on a robotic radiosurgery system (CyberKnife G4) in 2012. The results warranted further investigation of this treatment. Here we compare dosimetrically three possible treatment delivery platforms for STAR.The anatomy and target volume of the first treated patient were used for this study. A dose of 25 Gy in one fraction was prescribed to the planning target volume (PTV). Treatment plans were created on three treatment platforms: CyberKnife G4 system with Iris collimator (Multiplan, V. 4.6)(Plan #1), CyberKnife M6 system with InCise 2(TM) multileaf collimator (Multiplan V. 5.3)(Plan #2) and Varian TrueBeam(TM) STx with HD 120(TM) MLC and 10MV flattening filter free (FFF) beam (Eclipse planning system, V.11) (Plan #3 coplanar and #4 noncoplanar VMAT plans). The four plans were compared by prescription isodose line, plan conformity index, dose gradient, as well as dose to the nearby critical structures. To assess the delivery efficiency, planned monitor units (MU) and estimated treatment time were evaluated.Plans #1-4 delivered 25 Gy to the PTV to the 75.0%, 83.0%, 84.3%, and 84.9% isodose lines and with conformity indices of 1.19, 1.16, 1.05, and 1.05, respectively. The dose gradients for plans #1-4 were 3.62, 3.42, 3.93, and 3.73 with the CyberKnife MLC plan (Plan #2) the best, and the TrueBeam(TM) STx co-planar plan (Plan #3) the worst. The dose to nearby critical structures (lung, stomach, bowel, and esophagus) were all well within tolerance. The MUs for plans #1-4 were 27671, 16522, 6275, and 6004 for an estimated total-treatment-time/beam-delivery-time of 99/69, 65/35, 37/7, and 56/6 minutes, respectively, under the assumption of 30 minutes pretreatment setup time. For VMAT gated delivery, a 40% duty cycle, 2400MU/minute dose rate, and an extra 10 minutes per extra arc were assumed.Clinically acceptable plans were created with all three platforms. Plans with MLC were considerably more efficient in MU. CyberKnife M6 with InCise 2(TM) collimator provided the most conformal plan (steepest dose drop-off) with significantly reduced MU and treatment time. VMAT plans were most efficient in MU and delivery time. Fluoroscopic image guidance removes the need for additional fiducial marker placement; however, benefits may be moderated by worse dose gradient and more operator-dependent motion management by gated delivery.

View details for DOI 10.7759/cureus.694

View details for PubMedID 27570715

View details for PubMedCentralID PMC4996541

Abstract

Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n=21, V60BED3 4.1% TLV).Median CT follow-up was 15months. Median volume reduction of treated lobes was 4.5% of TLV (range 0.01-13.0%), or ~9% of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2% TLV (-4.6-9.9%; ~4% ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX=20-100 Gy, R (2) =0.52-0.55, p<0.0001) and smaller with lower pre-treatment FEV1% (R (2) =0.11, p=0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

View details for DOI 10.1186/s13014-016-0616-8

View details for PubMedID 26975700

Abstract

We present the case of a 42-year-old woman with metastatic synovial sarcoma of parotid origin, treated definitively with chemoradiation, who subsequently developed oligometastatic disease limited to the lungs. She underwent multiple left and right lung wedge resections and left lower lobectomy, followed by right lower lobe stereotactic ablative radiotherapy (SABR), 54 Gy in three fractions to a right lower lobe lesion abutting the chest wall. Two years later, she was treated with cryoablation for a separate right upper lobe nodule abutting the chest wall. Two months later, she presented with acute shortness of breath, pleuritic chest pain, decreased peripheral blood O2 saturation, and productive cough. A computed tomography (CT) scan demonstrated severe chest wall necrosis in the area of recent cryoablation that, in retrospect, also received a significant radiation dose from her prior SABR. This case demonstrates that clinicians should exercise caution in using cryoablation when treating lung tumors abutting a previously irradiated chest wall. Note: Drs. Loo and Shah contributed equally as co-senior authors.

View details for DOI 10.7759/cureus.477

View details for PubMedID 27004154

View details for PubMedCentralID PMC4780688

Abstract

Modestly hypofractionated radiation therapy (HypoRT; 60-66 Gy in 3-Gy fractions) allows patients with locally advanced thoracic tumors and poor performance status to complete treatment within a shorter period without concurrent chemotherapy. We evaluated the outcomes and imaging prognostic factors of HypoRT.We retrospectively reviewed the data from all patients with primary and metastatic intrathoracic tumors treated with HypoRT from 2006 to 2012. We analyzed the survival and toxicity outcomes, including overall survival (OS), progression-free survival (PFS), local recurrence (LR), and distant metastasis. We also evaluated the following tumor metrics in an exploratory analysis: gross tumor volume (GTV), maximum standardized uptake value (SUVMax), and metabolic tumor volume using a threshold of 50% of the SUVMax (MTV50%) or the maximum gradient of fluorine-18 fluorodeoxyglucose uptake (MTVEdge). We assessed the association of these metrics and their changes from before to mid-RT using positron emission tomography-computed tomography (PET-CT) with OS and PFS.We identified 29 patients, all with pre-RT and 20 with mid-RT PET-CT scans. The median follow-up period was 15 months. The 2-year overall and non-small-cell lung cancer-only rate for OS, PFS, and LR, was 59% and 59%, 52% and 41%, and 27% and 32%, respectively. No grade 3 toxicities developed. The median decrease in GTV, SUVMax, and MTVEdge was 11%, 24%, and 18%, respectively. Inferior OS was associated with a larger pre-RT MTVEdge (P= .005) and pre-RT MTV50% (P= .007). Inferior PFS was associated with a larger mid-RT SUVMax (P= .003).These findings add to the growing body of data demonstrating promising outcomes and limited toxicity with HypoRT. The pre- and mid-RT PET-CT metrics could be useful for prognostic stratification in future clinical trials.

View details for DOI 10.1016/j.cllc.2015.01.007

View details for PubMedID 25770888

View details for DOI 10.1016/j.ijrobp.2015.07.1738

View details for Web of Science ID 000373215301232

View details for DOI 10.1016/j.ijrobp.2015.07.1603

View details for Web of Science ID 000373215301101

View details for DOI 10.1016/j.ijrobp.2015.07.1628

View details for Web of Science ID 000373215301125

View details for DOI 10.1097/JTO.0000000000000623

View details for PubMedID 26536199

Abstract

The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans.Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent.Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent.For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed.

View details for DOI 10.1016/j.prro.2015.05.008

View details for PubMedID 26231596

Abstract

Treatmentregimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC.Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60Gy.Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5months, there were 93 grade3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade 3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade 3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6months with no significant differences between dose levels (P=.59).Precision hypofractionated radiation therapy consisting of 60Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.

View details for DOI 10.1016/j.ijrobp.2015.05.004

View details for PubMedID 26279026

Abstract

Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes.We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses.We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at /=10 (BED10) of <100Gy versus BED10 of 100Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed.SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation.

View details for DOI 10.1016/j.ijrobp.2015.04.004

View details for Web of Science ID 000357900600024

View details for PubMedID 26025776

Abstract

In this paper we present a novel technique for characterizing and classifying 3D textured volumes belonging to different lung tissue types in 3D CT images. We build a volume-based 3D descriptor, robust to changes of size, rigid spatial transformations and texture variability, thanks to the integration of Riesz-wavelet features within a Covariance-based descriptor formulation. 3D Riesz features characterize the morphology of tissue density due to their response to changes in intensity in CT images. These features are encoded in a Covariance-based descriptor formulation: this provides a compact and flexible representation thanks to the use of feature variations rather than dense features themselves and adds robustness to spatial changes. Furthermore, the particular symmetric definite positive matrix form of these descriptors causes them to lay in a Riemannian manifold. Thus, descriptors can be compared with analytical measures, and accurate techniques from machine learning and clustering can be adapted to their spatial domain. Additionally we present a classification model following a "Bag of Covariance Descriptors" paradigm in order to distinguish three different nodule tissue types in CT: solid, ground-glass opacity, and healthy lung. The method is evaluated on top of an acquired dataset of 95 patients with manually delineated ground truth by radiation oncology specialists in 3D, and quantitative sensitivity and specificity values are presented.

View details for DOI 10.1109/EMBC.2015.7320226

View details for PubMedID 26738126

Abstract

Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

View details for DOI 10.1016/j.ijrobp.2015.02.016

View details for PubMedID 26068491

Abstract

To determine whether regional ventilation, as measured using 4-dimensional computed tomography (4D-CT), declines after radiation therapy (RT).We analyzed pretreatment 4D-CT scans associated with 2 RT courses. We quantified regional pulmonary function over equivalent dose in 2Gy (EQD2/=3) intervals of 0 to 5Gy, 5 to 20Gy, 20 to 40Gy, and >40Gy using percentile-normalized intensity-based (VentInt) and Jacobian-based (VentJac) ventilation metrics. We modeled the impact of dose on mean ventilation (Vent) and regional tidal volume (rTV: tidal volume [TV] within a dose interval normalized to total lung TV). We also identified clinical and dosimetric factors that affected regional ventilation changes (Vent and rTV) after RT for the >20Gy dose interval.After RT, VentInt exhibited statistically significant dose-dependent declines within the 20 to 40Gy (-5.0%; P=.03) and >40Gy (-6.8%; P<.01) intervals. VentJac exhibited a declining trend after RT only for the >40Gy interval (-4.6%; P=.07). Factors associated with VentInt for the >20Gy dose interval included airway stenosis progression (P=.03) and gross tumor volume (P=.09). Both rTVInt and rTVJac were associated with small (<2%) but significant declines after RT for 20 to 40Gy and >40Gy intervals. Factors associated with declining rTVInt (P<.05) for the >20Gy dose interval included airway stenosis progression, greater V20 (volume of lung receiving >20Gy), and smaller fraction of emphysema in V20. The association between the absence of chronic obstructive pulmonary disease and declining rTV trended toward significance (P=.09).Regional ventilation, as measured using 4D-CT, demonstrates a dose-dependent decline after RT. Our results support the use of 4D-CT ventilation imaging for monitoring regional pulmonary function change after RT.

View details for DOI 10.1016/j.ijrobp.2015.02.037

View details for Web of Science ID 000355636800032

View details for PubMedID 25936813

Abstract

Treatment of central and ultra-central lung tumors with stereotactic ablative radiotherapy (SABR) remains controversial due to risks of treatment-related toxicities compared with peripheral tumors. Here we report our institution's experience in treating central and ultra-central lung tumor patients with SABR.We retrospectively reviewed outcomes in 68 patients with single lung tumors, 34 central and 34 peripheral, all treated with SABR consisting of 50 Gy in 4-5 fractions. Tumor centrality was defined per the RTOG 0813 protocol. We defined "ultra-central" tumors as those with GTV directly abutting the central airway.Median follow-up time was 18.4 months and median overall survival was 38.1 months. Two-year overall survival was similar between ultra-central, central, and peripheral NSCLC (80.0% vs. 63.2% vs. 86.6%, P=0.62), as was 2-year local failure (0% vs. 10.0% vs. 16.3%, P=0.64). Toxicity rates were low and comparable between the three groups, with only two cases of grade 3 toxicity (chest wall pain), and one case of grade 4 toxicity (pneumonitis) observed. Patients with ultra-central tumors experienced no symptomatic toxicities over a median follow-up time of 23.6 months. Dosimetric analysis revealed that RTOG 0813 central airway dose constraints were frequently not achieved in central tumor treatment plans, but this did not correlate with increased toxicity rate.Patients with central and ultra-central lung tumors treated with SABR (50 Gy in 4-5 fractions) experienced few toxicities and good outcomes, similar to patients with peripheral lung tumors.

View details for DOI 10.1016/j.lungcan.2015.04.014

View details for Web of Science ID 000356546300010

View details for PubMedID 25997421

Abstract

To analyze pooled clinical data using six radiobiological models and to understand the relationship between BED and TCP for SBRT of early-stage NSCLC.The clinical data of 1- , 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data from 46 studies were collected for SBRT of early stage (T1 and T2) NSCLC. The TCP data were separated for Stage T1 and T2 tumors if possible. BED was calculated at isocenters using six radiobiological models. Model parameters were determined from a fit to the TCP data using the least chi-square (2) method with one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately.The fits to the clinic data yield consistent results of large / ratios of about 23 Gy for all models. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (5 fractions) to achieve the optimal TCP when compared to the T1 tumors. Sample fractionation schemes were estimated based the determined model parameters for the regrowth model.A systematic analysis of a large set clinical data using six radiobiological models shows that local TCP for SBRT of early stage NSCLC has strong dependence on BED with large / ratios of about 23 Gy. The six models considered predict that a BED of 80 Gy is sufficient to achieve a 95% TCP. The regrowth model leads to better fit to the clinical data, the LQ model is the simplest and indistinguishable with remaining models. Sample fractionation regimens that can yield TCPs larger than 95% were estimated.

View details for DOI 10.1118/1.4926119

View details for PubMedID 26129419

Abstract

To test the hypothesis: 4D-CT ventilation imaging can show the known effects of radiotherapy on lung function: (1) radiation-induced ventilation reductions, and (2) ventilation increases caused by tumor regression.Repeat 4D-CT scans (pre-, mid- and/or post-treatment) were acquired prospectively for 11 thoracic cancer patients in an IRB-approved clinical trial. A ventilation image for each time point was created using deformable image registration and the Hounsfield unit (HU)-based or Jacobian-based metric. The 11 patients were divided into two subgroups based on tumor volume reduction using a threshold of 5 cm(3). To quantify radiation-induced ventilation reduction, six patients who showed a small tumor volume reduction (<5 cm(3)) were analyzed for dose-response relationships. To investigate ventilation increase caused by tumor regression, two of the other five patients were analyzed to compare ventilation changes in the lung lobes affected and unaffected by the tumor. The remaining three patients were excluded because there were no unaffected lobes.Dose-dependent reductions of HU-based ventilation were observed in a majority of the patient-specific dose-response curves and in the population-based dose-response curve, whereas no clear relationship was seen for Jacobian-based ventilation. The post-treatment population-based dose-response curve of HU-based ventilation demonstrated the average ventilation reductions of 20.97.0% at 35-40 Gy (equivalent dose in 2-Gy fractions, EQD2), and 40.622.9% at 75-80 Gy EQD2. Remarkable ventilation increases in the affected lobes were observed for the two patients who showed an average tumor volume reduction of 37.1 cm(3) and re-opening airways. The mid-treatment increase in HU-based ventilation of patient 3 was 100.4% in the affected lobes, which was considerably greater than 7.8% in the unaffected lobes.This study has demonstrated that 4D-CT ventilation imaging shows the known effects of radiotherapy on lung function: radiation-induced ventilation reduction and ventilation increase caused by tumor regression, providing validation for 4D-CT ventilation imaging. This study was supported in part by a National Lung Cancer Partnership Young Investigator Research grant.

View details for DOI 10.1118/1.4925754

View details for PubMedID 26129054

Abstract

To evaluate the performance of 100-120 MeV very-high energy electron (VHEE) scanning pencil beams to radiotherapy by means of Monte Carlo (MC) simulations.We selected five clinical cases with target sizes of 1.2 cm(3) to 990.4 cm(3). We calculated VHEE treatment plans using the MC EGSnrc code implemented in a MATLAB-based graphical user interface developed by our group. We generated phase space data for beam energies: 100 and 120 MeV and pencil beam spot sizes of 1, 3, and 5 mm at FWHM. The number of equidistant beams considered in this work was 16 or 32. Dose was calculated and then imported into a research version of RayStation where treatment plan optimization was performed. We compared the VHEE plans with the clinically delivered volumetric modulated arc therapy (VMAT) plan to evaluate VHEE plans performance.VHEE plans provided the same PTV coverage and dose homogeneity than VMAT plans for all the cases. In average, the mean dose to organs at risk (OARs) was 24% lower for the VHEE plans. The structures that benefited the most from using VHEE were: large bowel for the esophagus case, chest wall for the liver case, brainstem for the acoustic case, carina for the lung case, and genitalia for the anal case, with 23.7-34.6% lower dose. VHEE dose distributions were more conformal than VMAT solution as confirmed by conformity indices CI100 and CI50. Integral dose to the body was in average 19.6% (9.2%-36.5%) lower for the VHEE plans.We have shown that VHEE plans resulted in similar or superior dose distributions compared to clinical VMAT plans for five different cases and a wide range of target volumes, including a case with a small target (1.2 cm(3)), which represents a challenge for VMAT planning and might require the use of more complex non-coplanar VMAT plans. B Palma: None. M Bazalova: None. B Hardemark: Employee, RaySearch Laboratories AB. E Hynning: Employee, RaySearch Laboratories AB. B Qu: None. B Loo Jr.: Research support, RaySearch, Varian. P Maxim: Research support, RaySearch, Varian.

View details for DOI 10.1118/1.4925419

View details for PubMedID 26128721

Abstract

The advent of electromagnetic navigation bronchoscopy has enabled minimally invasive access to peripheral lung tumors previously inaccessible by optical bronchoscopes. As an adjunct to Stereotactic Ablative Radiosurgery (SABR), implantation of HDR catheters can provide focal treatments for multiple metastases and sites of retreatments. The authors evaluate a procedure to deliver ablative doses via Electromagnetically-Guided HDR (EMG-HDR) to lung metastases, quantify the resulting dosimetry, and assess its role in the comprehensive treatment of lung cancer.A retrospective study was conducted on ten patients, who, from 2009 to 2011, received a hypo-fractionated SABR regimen with 6MV VMAT to lesions in various lobes ranging from 1.5 to 20 cc in volume. A CT visible pathway was delineated for EM guided placement of an HDR applicator (catheter) and dwell times were optimized to ensure at least 98% prescription dose coverage of the GTV. Normal tissue doses were calculated using inhomogeneity corrections via a grid-based Boltzmann solver (Acuros_BV_1.5.0).With EMG-HDR, an average of 83% (+/-9% standard deviation) of each patient's GTV received over 200% of the prescription dose, as compared to SABR where the patients received an average maximum dose of 125% (+/-5%). EMG-HDR enabled a 59% (+/-12%) decrease in the aorta maximum dose, a 63% (+/-26%) decrease in the spinal cord max dose, and 57% (+/-23%) and 70% (+/-17%) decreases in the volume of the body receiving over 50% and 25% of the prescription dose, respectively.EMG-HDR enables delivery of higher ablative doses to the GTV, while concurrently reducing surrounding normal tissue doses. The single catheter approach shown here is limited to targets smaller than 20 cc. As such, the technique enables ablation of small lesions and a potentially safe and effective retreatment option in situations where external beam utility is limited by normal tissue constraints.

View details for DOI 10.1118/1.4925544

View details for PubMedID 26128845

Abstract

Elasticity may distinguish malignant from benign pulmonary nodules. To compare determining of malignant pulmonary nodule (MPN) elasticity from four dimensional computed tomography (4D CT) images versus inhale/exhale breath-hold CT images.We analyzed phase 00 and 50 of 4D CT and deep inhale and natural exhale of breath-hold CT images of 30 MPN treated with stereotactic ablative radiotherapy (SABR). The radius of the smallest MPN was 0.3 cm while the biggest one was 2.1 cm. An intensity based deformable image registration (DIR) workflow was applied to the 4D CT and breath-hold images to determine the volumes of the MPNs and a 1 cm ring of surrounding lung tissue (ring) in each state. Next, an elasticity parameter was derived by calculating the ratio of the volume changes of MPN (exhale:inhale or phase50:phase00) to that of a 1 cm ring of lung tissue surrounding the MPN. The proposed formulation of elasticity enables us to compare volume changes of two different MPN in two different locations of lung.The calculated volume ratio of MPNs from 4D CT (phase50:phase00) and breath-hold images (exhale:inhale) was 1.000.23 and 0.950.11, respectively. It shows the stiffness of MPN and comparably bigger volume changes of MPN in breath-hold images because of the deeper degree of inhalation. The calculated elasticity of MPNs from 4D CT and breath-hold images was 1.120.22 and 1.230.26, respectively. For five patients who have had two MPN in their lung, calculated elasticity of tumor A and tumor B follows same trend in both 4D CT and breath-hold images.We showed that 4D CT and breath-hold images are comparable in the ability to calculate the elasticity of MPN. This study has been supported by Department of Defense LCRP 2011 #W81XWH-12-1-0286.

View details for DOI 10.1118/1.4925257

View details for PubMedID 26128555

Abstract

It has been demonstrated that the use of noncoplanar beams in radiation therapy may Result in dose distributions that are comparable or better than standard coplanar beams [Pugachev, 2001]. A radiation therapy system designed with a noncoplanar beam geometry could allow for a full ring diagnostic quality imaging system to be placed around the patient. Additionally, if the noncoplanar beams were fixed in number and in their angle with respect to the patient's axial plane, then both treatment and imaging could be achieved concurrently without the need for moving parts, which could greatly reduce treatment times. For such a system to be designed, it is necessary to determine the appropriate number of beams and the beam angles to achieve optimal dose distributions. For simplicity, the beam angles are assumed to be equiangular in the patient's axial plane, and only the beam angle with respect to the axial plane are varied. This study aims to investigate the dose distributions produced by equiangular noncoplanar beams for multiple beam numbers and beam angles, and to compare these dose distributions with distributions achieved in coplanar volumetric arc therapy (VMAT).Dose distributions produced by noncoplanar beams were calculated using the Varian Eclipse treatment planning system by varying the gantry, collimator, and couch angles to simulate the noncoplanar delivery method. Noncoplanar intensity-modulated (NC-IMRT) beams using 8, 12, and 16 beams with angles varying from 45 degrees to 54 with respect to the patient's axial plane were studied.The NC-IMRT beams produced dose distributions comparable to VMAT plans for a number of treatment sites, and were capable of meeting similar dose-volume histogram constraints.This study has demonstrated that a noncoplanar beam delivery method with fixed beam numbers and beam angles is capable of delivering dose distributions comparable to VMAT plans currently in use.

View details for DOI 10.1118/1.4924876

View details for PubMedID 26128177

Abstract

To predict response to radiation treatment using computational FDG-PET and CT images in locally advanced head and neck cancer (HNC).68 patients with State III-IVB HNC treated with chemoradiation were included in this retrospective study. For each patient, we analyzed primary tumor and lymph nodes on PET and CT scans acquired both prior to and during radiation treatment, which led to 8 combinations of image datasets. From each image set, we extracted high-throughput, radiomic features of the following types: statistical, morphological, textural, histogram, and wavelet, resulting in a total of 437 features. We then performed unsupervised redundancy removal and stability test on these features. To avoid over-fitting, we trained a logistic regression model with simultaneous feature selection based on least absolute shrinkage and selection operator (LASSO). To objectively evaluate the prediction ability, we performed 5-fold cross validation (CV) with 50 random repeats of stratified bootstrapping. Feature selection and model training was solely conducted on the training set and independently validated on the holdout test set. Receiver operating characteristic (ROC) curve of the pooled Result and the area under the ROC curve (AUC) was calculated as figure of merit.For predicting local-regional recurrence, our model built on pre-treatment PET of lymph nodes achieved the best performance (AUC=0.762) on 5-fold CV, which compared favorably with node volume and SUVmax (AUC=0.704 and 0.449, p<0.001). Wavelet coefficients turned out to be the most predictive features. Prediction of distant recurrence showed a similar trend, in which pre-treatment PET features of lymph nodes had the highest AUC of 0.705.The radiomics approach identified novel imaging features that are predictive to radiation treatment response. If prospectively validated in larger cohorts, they could aid in risk-adaptive treatment of HNC.

View details for DOI 10.1118/1.4925515

View details for PubMedID 26128812

Abstract

Integration of coordinated robotic table motion with inversely-planned arc delivery has the potential to resolve table-top delivery limitations of large-field treatments such as Total Body Irradiation (TBI), Total Lymphoid Irradiation (TLI), and Cranial-Spinal Irradiation (CSI). We formulate the foundation for Trajectory Modulated Arc Therapy (TMAT), and using Varian Developer Mode capabilities, experimentally investigate its practical implementation for such techniques.A MATLAB algorithm was developed for inverse planning optimization of the table motion, MLC positions, and gantry motion under extended-SSD geometry. To maximize the effective field size, delivery trajectories for TMAT TBI were formed with the table rotated at 270 IEC and dropped vertically to 152.5cm SSD. Preliminary testing of algorithm parameters was done through retrospective planning analysis. Robotic delivery was programmed using custom XML scripting on the TrueBeam Developer Mode platform. Final dose was calculated using the Eclipse AAA algorithm. Initial verification of delivery accuracy was measured using OSLDs on a solid water phantom of varying thickness.A comparison of DVH curves demonstrated that dynamic couch motion irradiation was sufficiently approximated by static control points spaced in intervals of less than 2cm. Optimized MLC motion decreased the average lung dose to 68.5% of the prescription dose. The programmed irradiation integrating coordinated table motion was deliverable on a TrueBeam STx linac in 6.7 min. With the couch translating under an open 10cmx20cm field angled at 10, OSLD measurements along the midline of a solid water phantom at depths of 3, 5, and 9cm were within 3% of the TPS AAA algorithm with an average deviation of 1.2%.A treatment planning and delivery system for Trajectory Modulated Arc Therapy of extended volumes has been established and experimentally demonstrated for TBI. Extension to other treatment techniques such as TLI and CSI is readily achievable through the developed platform. Grant Funding by Varian Medical Systems.

View details for DOI 10.1118/1.4925570

View details for PubMedID 26128865

Abstract

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

View details for PubMedID 25964637

Abstract

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

View details for Web of Science ID 000354283800004

Abstract

Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for early-stage non-small cell lung cancer. Although direct comparisons from randomized trials are not available, rates of both primary tumor control and distant metastasis are similar between SABR and surgery. Overall survival is lower after SABR compared with surgery, largely reflecting that a primary selection criterion for SABR has been medical inoperability because of decreased cardiopulmonary function and other comorbidities that lead to decreased survival independent of non-small cell lung cancer. Survival outcomes between SABR and surgery are much more similar in propensity-matched cohorts. Newer potential indications for SABR include treatment of operable patients; of oligometastatic lung cancer, in which SABR has emerged as an alternative to metastasectomy; and of oligoprogressive lung cancer, an attractive concept especially as improved personalized systemic therapies emerge, and prospective trials are currently being conducted in these settings. Although toxicity in modern series is low, SABR is clearly capable of producing fatal complications, and understanding the risk factors and approaches for mitigating them has been emerging in recent years. Thus, appropriate patient selection is a vital, evolving, and controversial topic.

View details for DOI 10.1016/j.semradonc.2014.11.005

View details for PubMedID 25771411

Abstract

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

View details for Web of Science ID 000346190900012

View details for PubMedID 25505215

View details for DOI 10.1016/j.ijrobp.2014.08.315

View details for Web of Science ID 000346413500167

View details for DOI 10.1016/j.ijrobp.2014.08.145

View details for Web of Science ID 000346413500020

View details for DOI 10.1016/j.ijrobp.2014.08.027

View details for Web of Science ID 000346413500007

Abstract

Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non-small cell lung cancer (NSCLC)] and head and neck cancer patients.LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8(+) T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558-69. 2014 AACR.

View details for DOI 10.1158/1078-0432.CCR-14-1138

View details for PubMedID 25189484

View details for PubMedCentralID PMC4216761

Abstract

4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

View details for DOI 10.1016/j.ijrobp.2014.06.006

View details for Web of Science ID 000341994400026

Abstract

To compare real-time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT).Motion management with MLC tracking and gating was evaluated for four lung cancer patients. The IMAT plans were delivered to a dosimetric phantom mounted onto a 3D motion phantom performing patient-specific lung tumor motion. The MLC tracking system was guided by an optical system that used stereoscopic infrared (IR) cameras and five spherical reflecting markers attached to the dosimetric phantom. The gated delivery used a duty cycle of 35% and collected position data using an IR camera and two reflecting markers attached to a marker block.The average gamma index failure rate (2% and 2 mm criteria) was <0.01% with amplitude gating for all patients, and <0.1% with phase gating and <3.7% with MLC tracking for three of the four patients. One of the patients had an average failure rate of 15.1% with phase gating and 18.3% with MLC tracking. With no motion compensation, the average gamma index failure rate ranged from 7.1% to 46.9% for the different patients. Evaluation of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did not prolong the treatment time) or no motion compensation. For two of the patients, the different motion compensation techniques allowed for approximately the same margin reduction but for two of the patients, gating enabled a larger reduction of the margins than MLC tracking.Both gating and MLC tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the margins in some cases. MLC tracking did not prolong the treatment time compared to delivery with no motion compensation while gating had a considerably longer delivery time. In a clinical setting, the optical monitoring of the patients breathing would have to be correlated to the internal movements of the tumor.

View details for DOI 10.1118/1.4896024

View details for Web of Science ID 000343032400010

View details for PubMedID 25281946

View details for PubMedCentralID PMC4281086

Abstract

4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

View details for DOI 10.1016/j.ijrobp.2014.06.006

View details for PubMedID 25104070

Abstract

An increasing body of experience suggests that oligometastasis represents a minimal metastatic state with the potential for cure or prolonged survival in selected patients treated with radical local therapy to all identified sites of disease. The main clinical scenarios managed by thoracic oncology specialists are pulmonary oligometastases from primary malignancies of other anatomic sites and primary lung cancer with oligometastases to lung or other organs. Surgery has been a mainstay of treatment in these situations, with remarkably favorable outcomes following pulmonary metastasectomy in well-selected patient cohorts. As with early stage lung cancer in patients who are medically inoperable, stereotactic ablative radiotherapy is emerging as a prominent local treatment option for oligometastatic disease. We review the role and clinical experience of stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer.

View details for DOI 10.1097/JTO.0000000000000317

View details for Web of Science ID 000344368000006

Abstract

An increasing body of experience suggests that oligometastasis represents a minimal metastatic state with the potential for cure or prolonged survival in selected patients treated with radical local therapy to all identified sites of disease. The main clinical scenarios managed by thoracic oncology specialists are pulmonary oligometastases from primary malignancies of other anatomic sites and primary lung cancer with oligometastases to lung or other organs. Surgery has been a mainstay of treatment in these situations, with remarkably favorable outcomes following pulmonary metastasectomy in well-selected patient cohorts. As with early stage lung cancer in patients who are medically inoperable, stereotactic ablative radiotherapy is emerging as a prominent local treatment option for oligometastatic disease. We review the role and clinical experience of stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer.

View details for DOI 10.1097/JTO.0000000000000317

View details for PubMedID 25170641

View details for DOI 10.1016/j.ijrobp.2014.05.1857

View details for Web of Science ID 000342331402265

View details for Web of Science ID 000342331403092

View details for DOI 10.1016/j.ijrobp.2014.05.2283

View details for Web of Science ID 000342331403079

View details for DOI 10.1016/j.ijrobp.2014.05.2641

View details for Web of Science ID 000342331403435

View details for DOI 10.1016/j.ijrobp.2014.05.2647

View details for Web of Science ID 000342331403441

View details for DOI 10.1016/j.ijrobp.2014.05.721

View details for Web of Science ID 000342331400435

Abstract

Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and 6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, / = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade 3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED 60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

View details for DOI 10.1016/j.ijrobp.2014.05.025

View details for PubMedID 25015205

View details for Web of Science ID 000344627500044

View details for DOI 10.1016/j.ijrobp.2014.05.2342

View details for Web of Science ID 000342331403138

View details for DOI 10.1118/1.4894898

View details for Web of Science ID 000341068100118

Abstract

Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation.First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group.We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002).CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.

View details for PubMedID 25157764

Abstract

In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade 2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

View details for DOI 10.1097/JTO.0000000000000182

View details for Web of Science ID 000338025600015

Abstract

In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade 2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

View details for DOI 10.1097/JTO.0000000000000182

View details for PubMedID 24926543

Abstract

To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest.We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity.Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ-L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort.Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered.

View details for DOI 10.1016/j.prro.2013.08.005

View details for PubMedID 25012837

Abstract

The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.

View details for DOI 10.1016/j.cllc.2013.12.011

View details for PubMedID 24594400

View details for DOI 10.1118/1.4889666

View details for Web of Science ID 000438759605324

View details for DOI 10.1118/1.4887869

View details for Web of Science ID 000439377700038

View details for DOI 10.1118/1.4888605

View details for Web of Science ID 000436931100041

Abstract

To evaluate the efficacy of two noncommercial techniques for deep inspiration breathhold (DIBH) treatment of left-sided breast cancer (LSBC) using cine electronic portal imaging device (EPID) images.23,875 EPID images of 65 patients treated for LSBC at two different cancer treatment centers were retrieved. At the Milford Regional Cancer Center, DIBH stability was maintained by visual alignment of inroom lasers and patient skin tattoos (TAT). At the South Shore Hospital, a distance-measuring laser device (RTSSD) was implemented. For both centers,cine EPID images were acquired at least once per week during beam-on. Chest wall position relative to image boundary was measured and tracked over the course of treatment for every patient and treatment fraction for which data were acquired.Median intrabeam chest motion was 0.31 mm for the TAT method and 0.37 mm for the RTSSD method. The maximum excursions exceeded our treatment protocol threshold of 3 mm in 0.3% of cases (TAT) and 1.2% of cases (RTSSD). The authors did not observe a clinically significant difference between the two datasets.Both noncommercial techniques for monitoring the DIBH location provided DIBH stability within the predetermined treatment protocol parameters (<3 mm). The intreatment imaging offered by the EPID operating in cine mode facilitates retrospective analysis and validation of both techniques.

View details for DOI 10.1118/1.4862835

View details for Web of Science ID 000438759603034

View details for PubMedID 24506621

View details for PubMedCentralID PMC3977833

View details for DOI 10.1118/1.4894982

View details for Web of Science ID 000438759601086

View details for DOI 10.1118/1.4889712

View details for Web of Science ID 000438759601023

View details for DOI 10.1118/1.4889675

View details for Web of Science ID 000438759605333

View details for DOI 10.1118/1.4889499

View details for Web of Science ID 000438759605157

View details for DOI 10.1118/1.4889513

View details for Web of Science ID 000438726000033

View details for DOI 10.1118/1.4889223

View details for Web of Science ID 000438445400004

View details for Web of Science ID 000358613204749

Abstract

Patient comfort and positioning stability may be improved in the arms down (AD) compared with the typical arms up (AU) position in thoracic stereotactic ablative radiation therapy (SABR). We compared plan quality for AD vs AU when using volumetric modulated arc therapy (VMAT), and evaluated the sensitivity of AD plans to arm positioning variability.We took plans of 14 patients with 17 lung tumors treated with thoracic SABR using VMAT in the AD position and simulated the same treatments in the AU position by re-optimizing after digitally removing the ipsilateral arm. To evaluate the sensitivity of AD plans to arm positioning variability, all plans were recalculated without re-optimization after assigning water density to the ipsilateral arm (AD-W) and then digitally shifting the arm 2.5 cm anterolaterally (AD-WS).Between AD and AU plans, statistically significant but clinically insignificant (all original planning constraints met) differences were found for the following parameters: mean planning target volume maximum dose, difference of 2.3% of prescription dose (P = .049); mean intermediate dose conformity index, difference of 0.27 (P = .012); median percent lung volume receiving a minimum of 10, 20, and 30 Gy (V10, V20, and V30), differences of 0.5%, 0.2%, and 0.1%, respectively (P = .040, .007, and .001); and median spinal cord maximum dose, difference of 33.5 cGy (P = .017). Similarly, between AD-W and AD-WS plans, statistically significant but clinically insignificant differences were found for median lung V20 and V30, difference of 0.0% for both (P = .034 and .016, by matched pair analysis).Our exploratory planning study suggests that when using VMAT for lung tumor SABR, AD and AU positioning achieve clinically equivalent plan quality, and AD plans are insensitive to relatively large variability in arm position.

View details for DOI 10.1016/j.prro.2013.07.010

View details for PubMedID 24766687

Abstract

Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to 0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

View details for DOI 10.1038/nm.3519

View details for PubMedID 24705333

Abstract

Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC.We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments.The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT wasassociated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models.In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

View details for DOI 10.1016/j.ijrobp.2013.12.010

View details for PubMedID 24495591

Abstract

Cycle-to-cycle variations in respiratory motion can cause significant geometric and dosimetric errors in the administration of lung cancer radiation therapy. A common limitation of the current strategies for motion management is that they assume a constant, reproducible respiratory cycle. In this work, we investigate the feasibility of using rapid MRI for providing long-term imaging of the thorax in order to better capture cycle-to-cycle variations. Two nonsmall-cell lung cancer patients were imaged (free-breathing, no extrinsic contrast, and 1.5T scanner). A balanced steady-state-free-precession (b-SSFP) sequence was used to acquire cine-2D and cine-3D (4D) images. In the case of Patient 1 (right midlobe lesion, ~40mm diameter), tumor motion was well correlated with diaphragmatic motion. In the case of Patient 2, (left upper-lobe lesion, ~60mm diameter), tumor motion was poorly correlated with diaphragmatic motion. Furthermore, the motion of the tumor centroid was poorly correlated with the motion of individual points on the tumor boundary, indicating significant rotation and/or deformation. These studies indicate that image quality and acquisition speed of cine-2D MRI were adequate for motion monitoring. However, significant improvements are required to achieve comparable speeds for truly 4D MRI. Despite several challenges, rapid MRI offers a feasible and attractive tool for noninvasive, long-term motion monitoring.

View details for DOI 10.1155/2014/485067

View details for PubMedID 24524077

View details for PubMedCentralID PMC3913339

Abstract

To develop and clinically evaluate a volumetric imaging technique for assessing intrafraction geometric and dosimetric accuracy of stereotactic ablative radiation therapy (SABR).Twenty patients received SABR for lung tumors using volumetric modulated arc therapy (VMAT). At the beginning of each fraction, pretreatment cone beam computed tomography (CBCT) was used to align the soft-tissue tumor position with that in the planning CT. Concurrent with dose delivery, we acquired fluoroscopic radiograph projections during VMAT using the Varian on-board imaging system. Those kilovolt projections acquired during millivolt beam-on were automatically extracted, and intrafraction CBCT images were reconstructed using the filtered backprojection technique. We determined the time-averaged target shift during VMAT by calculating the center of mass of the tumor target in the intrafraction CBCT relative to the planning CT. To estimate the dosimetric impact of the target shift during treatment, we recalculated the dose to the GTV after shifting the entire patient anatomy according to the time-averaged target shift determined earlier.The mean target shift from intrafraction CBCT to planning CT was 1.6, 1.0, and 1.5mm; the 95th percentile shift was 5.2, 3.1, 3.6 mm; and the maximum shift was 5.7, 3.6, and 4.9 mm along the anterior-posterior, left-right, and superior-inferior directions. Thus, the time-averaged intrafraction gross tumor volume (GTV) position was always within the planning target volume. We observed some degree of target blurring in the intrafraction CBCT, indicating imperfect breath-hold reproducibility or residual motion of the GTV during treatment. By our estimated dose recalculation, the GTV was consistently covered by the prescription dose (PD), that is, V100% above 0.97 for all patients, and minimum dose to GTV >100% PD for 18 patients and >95% PD for all patients.Intrafraction CBCT during VMAT can provide geometric and dosimetric verification of SABR valuable for quality assurance and potentially for treatment adaptation.

View details for DOI 10.1016/j.ijrobp.2013.08.015

View details for PubMedID 24113060

Abstract

Four-dimensional (4D) computed tomography (CT) ventilation imaging is a novel promising technique for lung functional imaging. The current standard 4D CT technique using phase-based sorting frequently results in artifacts, which may deteriorate the accuracy of ventilation imaging. The purpose of this study was to quantify the variability of 4D CT ventilation imaging due to 4D CT sorting.4D CT image sets from nine lung cancer patients were each sorted by the phase-based method and anatomic similarity-based method, designed to reduce artifacts, with corresponding ventilation images created for each method. Artifacts in the resulting 4D CT images were quantified with the artifact score which was defined based on the difference between the normalized cross correlation for CT slices within a CT data segment and that for CT slices bordering the interface between adjacent CT data segments. The ventilation variation was quantified using voxel-based Spearman rank correlation coefficients for all lung voxels, and Dice similarity coefficients (DSC) for the spatial overlap of low-functional lung volumes. Furthermore, the correlations with matching single-photon emission CT (SPECT) ventilation images (assumed ground truth) were evaluated for three patients to investigate which sorting method provides higher physiologic accuracy.Anatomic similarity-based sorting reduced 4D CT artifacts compared to phase-based sorting (artifact score, 0.45 0.14 vs 0.58 0.24, p = 0.10 at peak-exhale; 0.63 0.19 vs 0.71 0.31, p = 0.25 at peak-inhale). The voxel-based correlation between the two ventilation images was 0.69 0.26 on average, ranging from 0.03 to 0.85. The DSC was 0.71 0.13 on average. Anatomic similarity-based sorting yielded significantly fewer lung voxels with paradoxical negative ventilation values than phase-based sorting (5.0 2.6% vs 9.7 8.4%, p = 0.05), and improved the correlation with SPECT ventilation regionally.The variability of 4D CT ventilation imaging due to 4D CT sorting was moderate overall and substantial in some cases, suggesting that 4D CT artifacts are an important source of variations in 4D CT ventilation imaging. Reduction of 4D CT artifacts provided more physiologically convincing and accurate ventilation estimates. Further studies are needed to confirm this result.

View details for DOI 10.1118/1.4820538

View details for PubMedID 24089909

View details for PubMedCentralID PMC3785523

View details for DOI 10.1016/j.ijrobp.2013.06.246

View details for Web of Science ID 000324503600233

View details for DOI 10.1016/j.ijrobp.2013.06.1955

View details for Web of Science ID 000324503602596

View details for DOI 10.1016/j.ijrobp.2013.06.1443

View details for Web of Science ID 000324503602097

View details for DOI 10.1016/j.ijrobp.2013.06.237

View details for Web of Science ID 000324503600224

View details for DOI 10.1016/j.prro.2012.09.003

View details for Web of Science ID 000422340000020

View details for DOI 10.1016/j.ijrobp.2013.06.1147

View details for Web of Science ID 000324503601520

Abstract

To determine the clinical impact of calculated dose differences between effective path length (EPL) and Monte Carlo (MC) algorithms in stereotactic ablative radiation therapy (SABR) of lung tumors.We retrospectively analyzed the treatment plans and clinical outcomes of 77 consecutive patients treated with SABR for 82 lung tumors between 2003 and 2009 at our institution. Sixty treatments were originally planned using EPL, and 22 using MC. All plans were recalculated for the same beam specifications using MC and EPL, respectively. The doses covering 95%, 50%, and 5% (D95, D50, D5, respectively) of the target volumes were compared between EPL and MC (assumed to be the actual delivered dose), both as physical dose and biologically effective dose. Time to local recurrence was correlated with dose by Cox regression analysis. The relationship between tumor control probability (TCP) and biologically effective dose was determined via logistic regression and used to estimate the TCP decrements due to prescribing by EPL calculations.EPL overestimated dose compared with MC in all tumor dose-volume histogram parameters in all plans. The difference was >10% of the MC D95 to the planning target volume and gross tumor volume in 60 of 82 (73%) and 52 of 82 plans (63%), respectively. Local recurrence occurred in 13 of 82 tumors. Controlling for gross tumor volume, higher physical and biologically effective planning target volume D95 correlated significantly with local control (P = .007 and P = .045, respectively). Compared with MC, prescribing based on EPL translated to a median TCP decrement of 4.3% (range, 1.2%-37%) and a >5% decrement in 46% of tumors.Clinical follow-up for local lung tumor control in a sizable cohort of patients treated with SABR demonstrates that EPL overestimates dose by amounts that substantially decrease TCP in a large proportion. EPL algorithms should be avoided for lung tumor SABR.

View details for DOI 10.1016/j.prro.2012.09.003

View details for PubMedID 24674401

Abstract

To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients 65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

View details for DOI 10.1016/j.amjoto.2013.03.007

View details for PubMedID 23583094

Abstract

Purpose: Emission guided radiation therapy (EGRT) is a new modality that uses PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along positron emission tomography (PET) lines of response (LORs) by a fast rotating ring therapy unit consisting of a linear accelerator (Linac) and PET detectors. The feasibility of tumor tracking and a primitive modulation method to compensate for attenuation have been demonstrated using a 4D digital phantom in our prior work. However, the essential capability of achieving dose modulation as in conventional intensity modulated radiation therapy (IMRT) treatments remains absent. In this work, the authors develop a planning scheme for EGRT to accomplish sophisticated intensity modulation based on an IMRT plan while preserving tumor tracking.Methods: The planning scheme utilizes a precomputed LOR response probability distribution to achieve desired IMRT planning modulation with effects of inhomogeneous attenuation and nonuniform background activity distribution accounted for. Evaluation studies are performed on a 4D digital patient with a simulated lung tumor and a clinical patient who has a moving breast cancer metastasis in the lung. The Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The IMRT plan is optimized for a planning target volume (PTV) that encompasses the tumor motion using the MOSEK package and a Pinnacle(3) workstation (Philips Healthcare, Fitchburg, WI) for digital and clinical patients, respectively. To obtain the emission data for both patients, the Geant4 application for tomographic emission (GATE) package and a commercial PET scanner are used. As a comparison, 3D and helical IMRT treatments covering the same PTV based on the same IMRT plan are simulated.Results: 3D and helical IMRT treatments show similar dose distribution. In the digital patient case, compared with the 3D IMRT treatment, EGRT achieves a 15.1% relative increase in dose to 95% of the gross tumor volume (GTV) and a 31.8% increase to 50% of the GTV. In the patient case, EGRT yields a 15.2% relative increase in dose to 95% of the GTV and a 20.7% increase to 50% of the GTV. The organs at risk (OARs) doses are kept similar or lower for EGRT in both cases. Tumor tracking is observed in the presence of planning modulation in all EGRT treatments.Conclusions: As compared to conventional IMRT treatments, the proposed EGRT planning scheme allows an escalated target dose while keeping dose to the OARs within the same planning limits. With the capabilities of incorporating planning modulation and accurate tumor tracking, EGRT has the potential to greatly improve targeting in radiation therapy and enable a practical and effective implementation of 4D radiation therapy for planning and delivery.

View details for DOI 10.1118/1.4812427

View details for Web of Science ID 000322735900013

View details for PubMedID 23927305

View details for PubMedCentralID PMC3732304

Abstract

These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail.

View details for PubMedID 23744864

Abstract

Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.

View details for Web of Science ID 000318752600007

View details for PubMedID 23667206

View details for DOI 10.1158/1538-7445.AM2013-3485

View details for Web of Science ID 000331220602190

Abstract

The purpose of this study was to quantify postimplantation migration of percutaneously implanted cylindrical gold seeds ("seeds") and platinum endovascular embolization coils ("coils") for tumor tracking in pulmonary stereotactic ablative radiotherapy (SABR). We retrospectively analyzed the migration of markers in 32 consecutive patients with computed tomography scans postimplantation and at simulation. We implanted 147 markers (59 seeds, 88 coils) in or around 34 pulmonary tumors over 32 procedures, with one lesion implanted twice. Marker coordinates were rigidly aligned by minimizing fiducial registration error (FRE), the root mean square of the differences in marker locations for each tumor between scans. To also evaluate whether single markers were responsible for most migration, we aligned with and without the outlier causing the largest FRE increase per tumor. We applied the resultant transformation to all markers. We evaluated migration of individual markers and FRE of each group. Median scan interval was 8 days. Median individual marker migration was 1.28 mm (interquartile range [IQR] 0.78-2.63 mm). Median lesion FRE was 1.56 mm (IQR 0.92-2.95 mm). Outlier identification yielded 1.03 mm median migration (IQR 0.52-2.21 mm) and 1.97 mm median FRE (IQR 1.44-4.32 mm). Outliers caused a mean and median shift in the centroid of 1.22 and 0.80 mm (95th percentile 2.52 mm). Seeds and coils had no statistically significant difference. Univariate analysis suggested no correlation of migration with the number of markers, contact with the chest wall, or time elapsed. Marker migration between implantation and simulation is limited and unlikely to cause geometric miss during tracking.

View details for DOI 10.1120/jacmp.v14i2.4046

View details for PubMedID 23470933

Abstract

PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy.Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan-Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Results: Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm(3) had worse PFS than did those with an MTV of 26 cm(3) or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02).MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

View details for DOI 10.2967/jnumed.112.109470

View details for PubMedID 23236018

Abstract

We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis.We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis.We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r=0.27, p-value=0.03) and not correlated with tumor diameter (r=0.07; p-value=0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease.CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.

View details for DOI 10.1371/journal.pone.0067733

View details for PubMedID 23861795

View details for PubMedCentralID PMC3702496

Abstract

Neuroendocrine tumors account for approximately 20% of lung cancers; most (15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.

View details for Web of Science ID 000313575200011

View details for PubMedID 23307984

View details for Web of Science ID 000313575200013

Abstract

The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity.A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved.Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking.Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.

View details for DOI 10.1378/chest.12-0790

View details for Web of Science ID 000312283800041

View details for PubMedID 23208335

Abstract

To test whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging metrics correlate with outcomes in patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).Fifty-four patients with stage I NSCLC underwent pre-SABR PET at simulation and/or post-SABR PET within 6 months. We analyzed maximum standardized uptake value (SUV(max)) and metabolic tumor volume defined using several thresholds (MTV50%, or MTV2, 4, 7, and 10). Endpoints included primary tumor control (PTC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We performed Kaplan-Meier, competing risk, and Cox proportional hazards survival analyses.Patients received 25-60 Gy in 1 to 5 fractions. Median follow-up time was 13.2 months. The 1-year estimated PTC, PFS, OS and CSS were 100, 83, 87 and 94%, respectively. Pre-treatment SUV(max) (p=0.014), MTV(7) (p=0.0077), and MTV(10) (p=0.0039) correlated significantly with OS. In the low-MTV(7)vs. high-MTV(7) sub-groups, 1-year estimated OS was 100 vs. 78% (p=0.0077) and CSS was 100 vs. 88% (p=0.082).In this hypothesis-generating study we identified multiple pre-treatment PET-CT metrics as potential predictors of OS and CSS in patients with NSCLC treated with SABR. These could aid risk-stratification and treatment individualization if validated prospectively.

View details for DOI 10.1016/j.lungcan.2012.08.016

View details for PubMedID 23009727

Abstract

A novel ventilation imaging method based on four-dimensional (4D) computed tomography (CT) has been applied to the field of radiation oncology. Understanding its reproducibility is a prerequisite for clinical applications. The purpose of this study was to quantify the reproducibility of 4D CT ventilation imaging over different days and the same session.Two ventilation images were created from repeat 4D CT scans acquired over the average time frames of 15 days for 6lung cancer patients and 5 minutes for another 6 patients. The reproducibility was quantified using the voxel-based Spearman rank correlation coefficients for all lung voxels and Dice similarity coefficients (DSC) for the spatial overlap of segmented high-, moderate-, and low-functional lung volumes. Furthermore, the relationship between the variation in abdominal motion range as a measure of the depth of breathing and variation in ventilation was evaluated using linear regression.The voxel-based correlation between the two ventilation images was moderate on average (0.50 0.15). The DSCs were also moderate for the high- (0.60 0.08), moderate- (0.46 0.06), and low-functional lung (0.58 0.09). No patients demonstrated strong correlations. The relationship between the motion range variation and ventilation variation was found to be moderate and significant.We investigated the reproducibility of 4D CT ventilation imaging over the time frames of 15 days and 5 minutes and found that it was only moderately reproducible. Respiratory variation during 4D CT scans was found to deteriorate the reproducibility. Improvement of 4D CT imaging is necessary to increase the reproducibility of 4D CT ventilation imaging.

View details for DOI 10.1016/j.acra.2012.07.006

View details for PubMedID 22975070

View details for Web of Science ID 000310542902315

View details for DOI 10.1016/j.ijrobp.2012.07.1621

View details for Web of Science ID 000310542902036

View details for DOI 10.1016/j.ijrobp.2012.07.1582

View details for Web of Science ID 000310542901708

View details for DOI 10.1016/j.ijrobp.2012.07.1523

View details for Web of Science ID 000310542901651

View details for Web of Science ID 000310542902020

View details for Web of Science ID 000310542902018

View details for Web of Science ID 000310542900386

View details for Web of Science ID 000310542900432

Abstract

Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.

View details for Web of Science ID 000309901900007

View details for PubMedID 23054877

Abstract

To correlate the prechemoradiotherapy (CRT) and post-CRT metabolic tumor volume (MTV) on positron emission tomography (PET) scanning with the pathologic response and survival in patients receiving preoperative CRT for esophageal cancer.The medical records of 37 patients with histologically confirmed Stage I-IVA esophageal cancer treated with CRT with or without surgical resection were reviewed. Of the 37 patients, 21 received preoperative CRT (57%) and 16 received definitive CRT (43%). All patients had a pre-CRT and 32 had a post-CRT PET scan. The MTV was measured on the pre-CRT PET and post-CRT PET scan, respectively, using a minimum standardized uptake value (SUV) threshold x, where x = 2, 2.5, 3, or the SUV maximum 50%. The total glycolytic activity (TGA(x)) was defined as the mean SUV MTV(x). The MTV ratio was defined as the pre-CRT PET MTV/post-CRT MTV. The SUV ratio was defined similarly. A single pathologist scored the pathologic response using a tumor regression grade (TRG) scale.The median follow-up was 1.5 years (range, 0.4-4.9). No significant correlation was found between any parameters on the pre-CRT PET scan and the TRG or overall survival (OS). Multiple post-CRT MTV values and post-TGA values correlated with the TRG and OS; however, the MTV(2.5(Post)) and TGA(2.5(Post)) had the greatest correlation. The MTV(2) ratio correlated with OS. The maximum SUV on either the pre-CRT and post-CRT PET scans or the maximum SUV ratio did not correlate with the TRG or OS. Patients treated preoperatively had survival similar compared with those treated definitively with a good PET response (p = 0.97) and significantly better than that of patients treated definitively with a poor PET response (p < 0.0001).The maximum SUV was not a predictive or prognostic parameter. The MTV(2.5) and TGA(2.5) were useful markers for predicting the response and survival on the post-CRT PET scan. The MTV(2) ratio also correlated with survival. Post-CRT PET can potentially guide therapy after CRT.

View details for DOI 10.1016/j.ijrobp.2011.12.029

View details for PubMedID 22381904

Abstract

Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

View details for DOI 10.1111/j.1442-2050.2011.01295.x

View details for PubMedID 22168251

Abstract

Patients with thoracic tumors that recur after irradiation currently have limited therapeutic options. Retreatment using stereotactic ablative radiotherapy (SABR) is appealing for these patients because of its high conformity but has not been studied extensively. Here we report our experience with SABR for lung tumors in previously irradiated regions.We conducted a retrospective study of patients with primary lung cancer or metastatic lung tumors treated with SABR. We identified 17 such tumors in 15 patients and compared their outcomes with those of a cohort of 135 previously unirradiated lung tumors treated with SABR during the same time period.Twelve-month local control (LC) for retreated tumors was 65.5%, compared with 92.1% for tumors receiving SABR as initial treatment. Twelve-month LC was significantly worse for reirradiated tumors in which the time interval between treatments was 16 months or less (46.7%), compared with those with longer intertreatment intervals (87.5%). SABR reirradiation did not lead to significant increases in treatment-related toxicity.SABR for locally recurrent lung tumors arising in previously irradiated fields seems to be feasible and safe for appropriately selected patients. LC of retreated lesions was significantly lower, likely owing to the lower doses used for retreatment. Shorter time to retreatment was associated with increased risk of local failure, suggesting that these tumors may be particularly radioresistant. Our findings suggest that dose escalation may improve LC while maintaining acceptable levels of toxicity for these patients.

View details for DOI 10.1097/JTO.0b013e31825f22ce

View details for Web of Science ID 000308073300024

View details for PubMedID 22895143

Abstract

We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans.From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume 50% of maximum SUV (SUV(max)). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV(max) over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival).The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV(max) (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03).Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

View details for DOI 10.1016/j.ijrobp.2011.10.022

View details for PubMedID 22270168

Abstract

To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.The average 3D distance between the markers and their ITVs was 0.8 0.5 mm (range, 0-1.7 mm) and was 2.1 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

View details for DOI 10.1016/j.ijrobp.2012.03.006

View details for PubMedID 22554582

Abstract

We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

View details for DOI 10.1016/j.ijrobp.2011.10.023

View details for PubMedID 22270174

Abstract

4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques.Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared.In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.790.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase.4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

View details for Web of Science ID 000308905804076

Abstract

Precise tumor delineation is important in thoracic radiation therapy planning, and using a 'lung detail' computed tomography (CT) reconstruction algorithm can assist in visualizing the tumor. We seek to determine the dosimetric impact of utilizing a lung detail algorithm versus a standard algorithm on calculated dose in radiation treatment planning.Ten patients, with 12 tumors, were analyzed in this study. Two CT scans, one reconstructed using a standard algorithm and one using a lung detail algorithm, were generated for each of 12 lung tumors. Treatment plans were calculated for each CT scan, with 7 tumors receiving stereotactic ablative radiotherapy (SABR) and 5 receiving intensity-modulated radiation therapy (IMRT). The Hounsfield unit (HU) and dose values for each voxel of the planning tumor volume (PTV), esophagus, spinal cord, and contralateral lung in both the CT and dose images were exported to MATLAB. For each contour, the voxel-by-voxel differences in the HU and dose distributions between the two scans were analyzed along with dose-volume histogram (DVH) data.Despite changes in HU values, the voxel-by-voxel analysis showed a negligible shift in dose values. The mean differences in dose for PTV, esophagus, spinal cord, and contralateral lung ranged from -12.12 to 22.57, -2.21 to 7.40, -0.50 to 5.93, and -1.12 to 7.41 cGy, respectively. DVH comparisons demonstrated no meaningful difference between plans. The mean PTV, esophagus, spinal cord, and contralateral lung doses measured from the DVH shifted between plans an average of 3.5, 2.93, -0.6 and -0.35 cGy, respectively. These dose differences are all less than 1% of the dose prescribed to the tumor and are not measurable by current technology.The lung detail reconstruction algorithm, when applied to thoracic radiation treatment planning CT scans, can help precisely delineate tumor with negligible dosimetric impact.

View details for PubMedID 28518919

View details for DOI 10.1118/1.4735873

View details for Web of Science ID 000308905805333

View details for DOI 10.1118/1.4736098

View details for Web of Science ID 000308905805557

Abstract

4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques.Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared.In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.790.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase.4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

View details for DOI 10.1118/1.4734673

View details for PubMedID 28517394

Abstract

Patients with stage IIIA non-small cell lung cancer, determined based on involvement of ipsilateral mediastinal lymph nodes, represent the most challenging management problem in this disease. Patients with this stage disease may have very different degrees of lymph node involvement. The pathologic confirmation of this involvement is a key step in the therapeutic decision. The difference in the degree of lymph node compromise has prognostic and treatment implications. Based on multiple considerations, patients can be treated with induction chemotherapy, chemoradiotherapy followed by surgery, or definitive chemoradiotherapy without surgery. Data derived from clinical trials have provided incomplete guidance for physicians and their patients. The best therapeutic plan is achieved through the multidisciplinary cooperation of a team specialized in lung cancer.

View details for Web of Science ID 000303557700006

View details for PubMedID 22570291

Abstract

We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients.Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUV mean), maximum SUV (SUV max) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS).Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUV max from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTV int/pre (p < 0.01), SUV mean int/pre (p < 0.05), SUV max int/pre (p = 0.01), and iSUV int/pre (p < 0.01). Absolute value SUV max from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV int/pre (p = 0.01), SUV max int/pre (p = 0.02) and iSUV int/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01).Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification.

View details for DOI 10.1186/1748-717X-7-5

View details for PubMedID 22260710

View details for DOI 10.1016/j.prro.2011.06.004

View details for Web of Science ID 000422312600005

Abstract

Metal artifacts can degrade computed tomographic (CT) simulation imaging and impair accurate delineation of tumors for radiation treatment planning purposes. We investigated a Digital Imaging and Communications in Medicine-based metal artifact reduction technique in tonsillar cancer delineation.Eight patients with significant artifact and tonsil cancer were evaluated. Each patient had a positron emission tomography (PET)-CT and a contrast-enhanced CT obtained at the same setting during radiotherapy simulation. The CTs were corrected for artifact using the metal deletion technique (MDT). Two radiation oncologists independently delineated primary gross tumor volumes (GTVs) for each patient on native (CTnonMDT), metal corrected (CTMDT), and reference standard (CTPET/nonMDT) imaging, 1 week apart. Mixed effects models were used to determine if differences among GTVs were statistically significant. Two diagnostic radiologists and 2 radiation oncologists independently qualitatively evaluated CTs for each patient. Ratings were on an ordinal scale from -3 to +3, denoting that CTMDT was markedly, moderately, or slightly worse or better than CTnonMDT. Scores were compared with a Wilcoxon signed-rank test.The GTVPET/nonMDT were significantly smaller than GTVnonMDT (P = .004) and trended to be smaller than GTVMDT (P = .084). The GTVnonMDT and GTVMDT were not significantly different (P = .93). There was no significant difference in the extent to which GTVnonMDT or GTVMDT encompassed GTVPET/nonMDT (P = .33). In the subjective assessment of image quality, CTMDT did not significantly outperform CTnonMDT. In the majority of cases, the observer rated the CTMDT equivalent to (53%) or slightly superior (41%) to the corresponding CTnonMDT.The MTD modified images did not produce GTVMDT that more closely reproduced GTVPET/nonMDT than did GTVnonMDT. Moreover, the MTD modified images were not judged to be significantly superior when compared to the uncorrected images in terms of subjective ability to visualize the tonsilar tumors. This study failed to demonstrate value of the adjunctive use of a CT corrected for artifacts in the tumor delineation process. Artifacts do make tumor delineation challenging, and further investigation of other body sites is warranted.

View details for DOI 10.1016/j.prro.2011.06.004

View details for PubMedID 24674033

Abstract

The aim of this study is to develop an automated method to objectively compare motion artifacts in two four-dimensional computed tomography (4D CT) image sets, and identify the one that would appear to human observers with fewer or smaller artifacts. Our proposed method is based on the difference of the normalized correlation coefficients between edge slices at couch transitions, which we hypothesize may be a suitable metric to identify motion artifacts. We evaluated our method using ten pairs of 4D CT image sets that showed subtle differences in artifacts between images in a pair, which were identifiable by human observers. One set of 4D CT images was sorted using breathing traces in which our clinically implemented 4D CT sorting software miscalculated the respiratory phase, which expectedly led to artifacts in the images. The other set of images consisted of the same images; however, these were sorted using the same breathing traces but with corrected phases. Next we calculated the normalized correlation coefficients between edge slices at all couch transitions for all respiratory phases in both image sets to evaluate for motion artifacts. For nine image set pairs, our method identified the 4D CT sets sorted using the breathing traces with the corrected respiratory phase to result in images with fewer or smaller artifacts, whereas for one image pair, no difference was noted. Two observers independently assessed the accuracy of our method. Both observers identified 9 image sets that were sorted using the breathing traces with corrected respiratory phase as having fewer or smaller artifacts. In summary, using the 4D CT data of ten pairs of 4D CT image sets, we have demonstrated proof of principle that our method is able to replicate the results of two human observers in identifying the image set with fewer or smaller artifacts.

View details for DOI 10.1120/jacmp.v13i6.3838

View details for PubMedID 23149777

View details for Web of Science ID 000299007500006

View details for PubMedID 22223867

Abstract

To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R(2) range 0.29-0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R(2)=0.63).Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.

View details for DOI 10.1016/j.radonc.2011.05.040

View details for PubMedID 21665308

Abstract

To evaluate the positioning accuracy of an optical positioning system for stereotactic radiosurgery in a pilot experience of optically guided, conventionally fractionated, radiotherapy for paranasal sinus and skull base tumors.Before each daily radiotherapy session, the positioning of 28 patients was set up using an optical positioning system. After this initial setup, the patients underwent standard on-board imaging that included daily orthogonal kilovoltage images and weekly cone beam computed tomography scans. Daily translational shifts were made after comparing the on-board images with the treatment planning computed tomography scans. These daily translational shifts represented the daily positional error in the optical tracking system and were recorded during the treatment course. For 13 patients treated with smaller fields, a three-degree of freedom (3DOF) head positioner was used for more accurate setup.The mean positional error for the optically guided system in patients with and without the 3DOF head positioner was 1.4 1.1 mm and 3.9 1.6 mm, respectively (p <.0001). The mean positional error drifted 0.11 mm/wk upward during the treatment course for patients using the 3DOF head positioner (p = .057). No positional drift was observed in the patients without the 3DOF head positioner.Our initial clinical experience with optically guided head-and-neck fractionated radiotherapy was promising and demonstrated clinical feasibility. The optically guided setup was especially useful when used in conjunction with the 3DOF head positioner and when it was recalibrated to the shifts using the weekly portal images.

View details for DOI 10.1016/j.ijrobp.2010.08.049

View details for Web of Science ID 000296823600035

View details for PubMedID 21543166

View details for DOI 10.1016/j.ijrobp.2011.05.023

View details for Web of Science ID 000296823600043

Abstract

Outcomes are suboptimal when molecularly targeted therapies are used in patient populations unselected for the molecular target. This pilot study examines the correlation of PET using (11)C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline ((11)C-PD153035), an imaging biomarker of epidermal growth factor receptor (EGFR), with outcomes in patients with non-small cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor erlotinib.Patients with advanced chemotherapy-refractory NSCLC were prospectively enrolled on a trial of erlotinib at a dose of 150 mg daily and imaged by (11)C-PD153035 PET/CT at baseline, after 1-2 wk, and after 6 wk from the start of treatment. Overall survival and progression-free survival (OS and PFS, respectively) times were correlated with the (11)C-PD153035 standardized uptake value (SUV) at each of the imaging times.Twenty-one patients were enrolled. Follow-up to progression was complete in all patients and to death in 18 of 21. By Cox regression analysis, baseline maximum SUV correlated strongly with OS and PFS (hazard ratio = 0.40, P = 0.002, and hazard ratio = 0.044, P < 0.001, respectively) independent of histology. Patients with higher maximum SUV (median) survived more than twice as long as patients with lower maximum SUV (median OS = 11.4 vs. 4.6 mo, P = 0.002; PFS = 4.4 vs. 1.8 mo, P < 0.001). However, (11)C-PD153035 uptake on follow-up scans was less well correlated with survival.Our preliminary results suggest (11)C-PD153035 PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC of adenocarcinoma or squamous histology likely to respond to the EGFR tyrosine kinase inhibitor but not for monitoring treatment response.

View details for DOI 10.2967/jnumed.111.092874

View details for Web of Science ID 000295537800016

View details for PubMedID 21903741

View details for DOI 10.3978/j.issn.2072-1439.2011.06.08

View details for PubMedID 22263081

View details for PubMedCentralID PMC3256516

Abstract

The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

View details for DOI 10.1016/j.cllc.2011.06.003

View details for PubMedID 21752720

Abstract

To compare the retention rates of two types of implanted fiducial markers for stereotactic ablative radiotherapy (SABR) of pulmonary tumors, smooth cylindrical gold "seed" markers ("seeds") and platinum endovascular embolization coils ("coils"), and to compare the complication rates associated with the respective implantation procedures.We retrospectively analyzed the retention of percutaneously implanted markers in 54 consecutive patients between January 2004 and June 2009. A total of 270 markers (129 seeds, 141 coils) were implanted in or around 60 pulmonary tumors over 59 procedures. Markers were implanted using a percutaneous approach under computed tomography (CT) guidance. Postimplantation and follow-up imaging studies were analyzed to score marker retention relative to the number of markers implanted. Markers remaining near the tumor were scored as retained. Markers in a distant location (e.g., pleural space) were scored as lost. CT imaging artifacts near markers were quantified on radiation therapy planning scans.Immediately after implantation, 140 of 141 coils (99.3%) were retained, compared to 110 of 129 seeds (85.3%); the difference was highly significant (p<0.0001). Of the total number of lost markers, 45% were reported lost during implantation, but 55% were lost immediately afterwards. No additional markers were lost on longer-term follow-up. Implanted lesions were peripherally located for both seeds (mean distance, 0.33 cm from pleural surface) and coils (0.34 cm) (p=0.96). Incidences of all pneumothorax (including asymptomatic) and pneumothorax requiring chest tube placement were lower in implantation of coils (23% and 3%, respectively) vs. seeds (54% and 29%, respectively; p=0.02 and 0.01). The degree of CT artifact was similar between marker types.Retention of CT-guided percutaneously implanted coils is significantly better than that of seed markers. Furthermore, implanting coils is at least as safe as implanting seeds. Using coils should permit implantation of fewer markers and require fewer repeat implantation procedures owing to lost markers.

View details for DOI 10.1016/j.ijrobp.2010.04.037

View details for PubMedID 20675070

Abstract

Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients.Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks).Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04).Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

View details for DOI 10.1016/j.ijrobp.2010.04.031

View details for PubMedID 20675073

View details for DOI 10.1016/j.ijrobp.2011.03.032

View details for Web of Science ID 000293207600049

Abstract

To explore the prognostic value of metabolic tumor volume measured on postradiation (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with head-and-neck cancer.Forty-seven patients with head-and-neck cancer who received pretreatment and posttreatment PET/computed tomography (CT) imaging along with definitive chemoradiotherapy were included in this study. The PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV(2.0)-MTV(4.0); where MTV(2.0) refers to the volume above a standardized uptake value threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox regression models were used to test for association between PET endpoints and disease-free survival and overall survival.Multiple postradiation PET endpoints correlated significantly with outcome; however, the most robust predictor of disease progression and death was MTV(2.0). An increase in MTV(2.0) of 21 cm(3) (difference between 75th and 25th percentiles) was associated with an increased risk of disease progression (hazard ratio [HR] = 2.5, p = 0.0001) and death (HR = 2.0, p = 0.003). In patients with nonnasopharyngeal carcinoma histology (n = 34), MTV(2.0) <18 cm(3) and MTV(2.0) 18 cm(3) yielded 2-year disease-free survival rates of 100% and 63%, respectively (p = 0.006) and 2-year overall survival rates of 100% and 81%, respectively (p = 0.009). There was no correlation between MTV(2.0) and disease-free survival or overall survival with nasopharyngeal carcinoma histology (n = 13). On multivariate analysis, only postradiation MTV(2.0) was predictive of disease-free survival (HR = 2.47, p = 0.0001) and overall survival (HR = 1.98, p = 0.003).Postradiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification and will be valuable in the future with risk-adapted therapies.

View details for DOI 10.1016/j.ijrobp.2010.01.057

View details for Web of Science ID 000290837100028

View details for PubMedID 20646870

View details for PubMedCentralID PMC2962876

View details for Web of Science ID 000208855803108

View details for Web of Science ID 000208855801215

View details for Web of Science ID 000208855803306

Abstract

The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

View details for DOI 10.1097/JTO.0b013e31821517db

View details for PubMedID 21774104

Abstract

Four-dimensional (4D) computed tomography (CT) has been widely used as a tool to characterize respiratory motion in radiotherapy. The two most commonly used 4D CT algorithms sort images by the associated respiratory phase or displacement into a predefined number of bins, and are prone to image artifacts at transitions between bed positions. The purpose of this work is to demonstrate a method of reducing motion artifacts in 4D CT by incorporating anatomic similarity into phase or displacement based sorting protocols.Ten patient datasets were retrospectively sorted using both the displacement and phase based sorting algorithms. Conventional sorting methods allow selection of only the nearest-neighbor image in time or displacement within each bin. In our method, for each bed position either the displacement or the phase defines the center of a bin range about which several candidate images are selected. The two dimensional correlation coefficients between slices bordering the interface between adjacent couch positions are then calculated for all candidate pairings. Two slices have a high correlation if they are anatomically similar. Candidates from each bin are then selected to maximize the slice correlation over the entire data set using the Dijkstra's shortest path algorithm. To assess the reduction of artifacts, two thoracic radiation oncologists independently compared the resorted 4D datasets pairwise with conventionally sorted datasets, blinded to the sorting method, to choose which had the least motion artifacts. Agreement between reviewers was evaluated using the weighted kappa score.Anatomically based image selection resulted in 4D CT datasets with significantly reduced motion artifacts with both displacement (P = 0.0063) and phase sorting (P = 0.00022). There was good agreement between the two reviewers, with complete agreement 34 times and complete disagreement 6 times.Optimized sorting using anatomic similarity significantly reduces 4D CT motion artifacts compared to conventional phase or displacement based sorting. This improved sorting algorithm is a straightforward extension of the two most common 4D CT sorting algorithms.

View details for DOI 10.1118/1.3577601

View details for Web of Science ID 000290625700016

View details for PubMedID 21776777

Abstract

A pulmonary ventilation imaging technique based on four-dimensional (4D) computed tomography (CT) has advantages over existing techniques. However, physiologically accurate 4D-CT ventilation imaging has not been achieved in patients. The purpose of this study was to evaluate 4D-CT ventilation imaging by correlating ventilation with emphysema. Emphysematous lung regions are less ventilated and can be used as surrogates for low ventilation. We tested the hypothesis: 4D-CT ventilation in emphysematous lung regions is significantly lower than in non-emphysematous regions. Four-dimensional CT ventilation images were created for 12 patients with emphysematous lung regions as observed on CT, using a total of four combinations of two deformable image registration (DIR) algorithms: surface-based (DIR(sur)) and volumetric (DIR(vol)), and two metrics: Hounsfield unit (HU) change (V(HU)) and Jacobian determinant of deformation (V(Jac)), yielding four ventilation image sets per patient. Emphysematous lung regions were detected by density masking. We tested our hypothesis using the one-tailed t-test. Visually, different DIR algorithms and metrics yielded spatially variant 4D-CT ventilation images. The mean ventilation values in emphysematous lung regions were consistently lower than in non-emphysematous regions for all the combinations of DIR algorithms and metrics. V(HU) resulted in statistically significant differences for both DIR(sur) (0.14 0.14 versus 0.29 0.16, p = 0.01) and DIR(vol) (0.13 0.13 versus 0.27 0.15, p < 0.01). However, V(Jac) resulted in non-significant differences for both DIR(sur) (0.15 0.07 versus 0.17 0.08, p = 0.20) and DIR(vol) (0.17 0.08 versus 0.19 0.09, p = 0.30). This study demonstrated the strong correlation between the HU-based 4D-CT ventilation and emphysema, which indicates the potential for HU-based 4D-CT ventilation imaging to achieve high physiologic accuracy. A further study is needed to confirm these results.

View details for DOI 10.1088/0031-9155/56/7/023

View details for Web of Science ID 000288506600026

View details for PubMedID 21411868

Abstract

Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation.A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions.Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10(5) over a distance of 130 m. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of 10(3) as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively.Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.

View details for DOI 10.1016/j.ijrobp.2010.10.007

View details for Web of Science ID 000288471500031

View details for PubMedID 21183291

View details for PubMedCentralID PMC3053128

Abstract

A novel pulmonary ventilation imaging technique based on four-dimensional (4D) CT has advantages over existing techniques and could be used for functional avoidance in radiotherapy. There are various deformable image registration (DIR) algorithms and two classes of ventilation metric that can be used for 4D-CT ventilation imaging, each yielding different images. The purpose of this study was to quantify the variability of the 4D-CT ventilation to DIR algorithms and metrics.4D-CT ventilation images were created for 12 patients using different combinations of two DIR algorithms, volumetric (DIR(vol)) and surface-based (DIR(sur)), yielding two displacement vector fields (DVFs) per patient (DVF(voI) and DVF(sur)), and two metrics, Hounsfield unit (HU) change (V(HU)) and Jacobian determinant of deformation (V(Jac)), yielding four ventilation image sets (V(HU)(vol), V(HU)(sur), V(Jac)(voI), and V(Jac)(sur). First DVF(vol) and DVF(sur) were compared visually and quantitatively to the length of 3D displacement vector difference. Second, four ventilation images were compared based on voxel-based Spearman's rank correlation coefficients and coefficients of variation as a measure of spatial heterogeneity. V(HU)(vol) was chosen as the reference for the comparison.The mean length of 3D vector difference between DVF(vol) and DVF(sur) was 2.0 +/- 1.1 mm on average, which was smaller than the voxel dimension of the image set and the variations. Visually, the reference V(HU)(vol) demonstrated similar regional distributions with V(HU)(sur); the reference, however, was markedly different from V(Jac)(vol) and V((Jac)(sur). The correlation coefficients of V(HU)(vol) with V(HU)(sur), V(Jac)(vol) and V(Jac)(sur) were 0.77 +/- 0.06, 0.25 +/- 0.06 and 0.15 +/- 0.07, respectively, indicating that the metric introduced larger variations in the ventilation images than the DIR algorithm. The spatial heterogeneities for V(HU)(vol), 'V(HU)(sur), V(Jac)(vol), and V(Jac)(sur) were 1.8 +/- 1.6, 1.8 +/- 1.5 (p = 0. 85), 0.6 +/- 0.2 (p = 0.02), and 0.7 +/- 0.2 (p = 0.03), respectively, also demonstrating that the metric introduced larger variations.4D-CT pulmonary ventilation images vary widely with DIR algorithms and metrics. Careful physiologic validation to determine the appropriate DIR algorithm and metric is needed prior to its applications.

View details for DOI 10.1118/1.3547719

View details for Web of Science ID 000287879400022

View details for PubMedID 21520845

View details for Web of Science ID 000295901600408

View details for DOI 10.1016/j.ijrobp.2011.06.164

View details for Web of Science ID 000296411700160

View details for DOI 10.1016/j.ijrobp.2011.06.500

View details for Web of Science ID 000296411700633

View details for DOI 10.1016/j.ijrobp.2011.06.1133

View details for Web of Science ID 000296411701317

View details for Web of Science ID 000296411701294

View details for Web of Science ID 000296411701270

View details for Web of Science ID 000296411701321

View details for Web of Science ID 000296411701313

View details for Web of Science ID 000296411701268

View details for Web of Science ID 000295901600319

Abstract

Managing target motion first requires understanding the nature of the motion characteristic of the tumor in the individual patient. It is important to have effective immobilization and patient training strategies to help reduce motion, and then to design appropriate margins and compensation for the residual motion that is quantified. Especially when considering complex, technically demanding treatments that require a degree of patient cooperation, careful patient selection is needed to ensure that the potential benefits of the treatment design are actually realized. Finally, accurate treatment hinges critically on verification - of overall positioning, of target and organ motion at the time of treatment, and of the performance of the selected treatment strategy. Properly selected imaging methods are central to this verification process. This discussion will present practical solutions for motion management and image guidance of radiotherapy for thoracic tumors, and most of these concepts are widely applicable to treatment of other tumor sites as well.

View details for Web of Science ID 000292117400013

View details for PubMedID 21625158

Abstract

Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

View details for DOI 10.1002/hed.21406

View details for PubMedID 20848427

Abstract

Stereotactic ablative radiotherapy (SABR) has emerged as a promising treatment for early stage non-small cell lung cancer, particularly for patients unable to tolerate surgical resection. High rates of local tumor control have been demonstrated with acceptable toxicity and the practical advantage of a short course of treatment. The CyberKnife image-guided robotic radiosurgery system has unique technical characteristics that make it well suited for SABR of tumors that move with breathing, including lung tumors. We review the qualities of the CyberKnife platform for lung tumor SABR, and provide a summary of clinical data using this system specifically.

View details for Web of Science ID 000284971100007

View details for PubMedID 21070081

Abstract

To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer.We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR.The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole.

View details for DOI 10.1016/j.ijrobp.2010.04.070

View details for Web of Science ID 000282147000002

View details for PubMedID 20832663

View details for PubMedCentralID PMC2939040

View details for DOI 10.1200/jco.2010.28.15_suppl.7080

View details for Web of Science ID 000208852004623

View details for DOI 10.1200/jco.2010.28.15_suppl.tps288

View details for Web of Science ID 000208852002288

Abstract

Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as one of the standard treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. Its use has also been explored in operable patients. A large body of experience, either from retrospective studies or clinical trials, has been accumulated over the years and more is known about the radiobiology, cancer biology, technical aspects, clinical outcomes, and toxicities of SBRT. This article provides updates of these aspects of SBRT for stage I NSCLC.

View details for PubMedID 20515609

Abstract

To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

View details for DOI 10.1016/j.ijrobp.2009.04.006

View details for PubMedID 19540068

View details for Web of Science ID 000288775701202

View details for DOI 10.1016/j.ijrobp.2010.07.636

View details for Web of Science ID 000288775700576

View details for DOI 10.1016/j.ijrobp.2010.07.450

View details for Web of Science ID 000288775700396

View details for DOI 10.1016/j.ijrobp.2010.07.1216

View details for Web of Science ID 000288775701207

View details for DOI 10.1007/978-4-431-98074-2_2

View details for Web of Science ID 000271884900002

View details for Web of Science ID 000288775701265

View details for Web of Science ID 000288775701074

View details for Web of Science ID 000288775701063

View details for Web of Science ID 000288775701162

View details for Web of Science ID 000288775700383

View details for Web of Science ID 000288775701011

View details for PubMedID 20009915

View details for DOI 10.1016/j.radonc.2009.08.024

View details for Web of Science ID 000272762900048

View details for PubMedID 19748142

Abstract

Critical advances in the treatment of patients with lung cancer have occurred in the past few years. The cooperative groups in North America and internationally have played crucial roles in these advances. The leaders of the groups meet on a regular basis to review the progress of their trials. However, they rarely have a chance to discuss all ongoing and planned trials, except at the annual Lung Cancer Congress held each June. This article captures this exchange from the 10th Annual Lung Cancer Congress held in June 2009. Exciting efforts are ongoing for all stages of non-small-cell lung cancer, small-cell lung cancer, and mesothelioma. A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit. Agents targeting the vascular endothelial growth factor (VEGF) pathway, including many tyrosine kinase inhibitors against the VEGF receptor, and those targeting the epidermal growth factor receptor pathway, are under extensive development with many combination trials ongoing.

View details for DOI 10.3816/CLC.2009.n.075

View details for PubMedID 19900856

View details for Web of Science ID 000269496002262

View details for Web of Science ID 000269496002765